Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.
ABSTRACT: Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-?-positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([18F]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau181. Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau181 levels were associated with higher MBI-C scores (??=?0.010, SE?=?0.003, p?=?0.003 and ??=?1.263, SE?=?0.446, p?=?0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (??=?0.009, p?=?0.009) and CSF P-tau181 (??=?0.408, p?=?0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.
Project description:<h4>Background and objectives</h4>Phosphorylated tau (p-tau) in CSF is considered an important biomarker in Alzheimer disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including p-tau at threonines 181 (p-tau181), 217 (p-tau217), and 231 (p-tau231). However, no studies have compared their diagnostic performance or association to β-amyloid (Aβ) and tau-PET. Understanding which p-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of p-tau181, p-tau217, and p-tau231 in CSF for AD and their association with Aβ and tau-PET.<h4>Methods</h4>A total of 629 participants in the Swedish BioFINDER-2 study were included (cognitively unimpaired, n = 334; Aβ-positive mild cognitive impairment, n = 84; AD dementia, n = 119; and non-AD disorders, n = 92). In addition to p-tau181 and p-tau217 measured using assays with the same detector antibodies from Eli Lilly (p-tau181<sub>Lilly</sub>, p-tau217<sub>Lilly</sub>) and p-tau231, we also included p-tau181 measurements from 2 commonly used assays (Innotest and Elecsys).<h4>Results</h4>Although all p-tau variants increased across the AD continuum, p-tau217<sub>Lilly</sub> showed the greatest dynamic range (13-fold increase vs 1.9-5.4-fold increase for other p-tau variants for AD dementia vs non-AD). P-Tau217<sub>Lilly</sub> showed stronger correlations with Aβ- and tau-PET (<i>p</i> < 0.0001). P-Tau217<sub>Lilly</sub> exhibited higher accuracy than other p-tau variants for separating AD dementia from non-AD (area under the curve [AUC], 0.98 vs 0.88 [<i>p</i> < 0.0001] - 0.96 [<i>p</i> < 0.05]) and for identifying Aβ-PET (AUC, 0.86 vs 0.74 [<i>p</i> < 0.0001] and 0.83 [<i>p</i> < 0.001]) and tau-PET positivity (AUC, 0.94 vs 0.80-0.92, <i>p</i> < 0.0001). Finally, p-Tau181<sub>Lilly</sub> generally performed better than the other p-tau181 assays (e.g., AD dementia vs non-AD, AUC, 0.96 vs 0.88 [p-tau181<sub>Innotest</sub>] and 0.89 [p-tau181<sub>Elecsys</sub>]; <i>p</i> < 0.0001).<h4>Discussion</h4>CSF p-tau217<sub>Lilly</sub> seems to be more useful than other included p-tau assays in the workup of AD. Varied results across p-tau181 assays highlights the importance of anti-tau antibodies for biomarker performance.<h4>Classification of evidence</h4>This study provides Class II evidence that p-tau217 provides higher diagnostic accuracy for diagnosis of AD dementia than p-tau181 or p-tau231.
Project description:<h4>Background/aims</h4>Disease-modifying therapy for Alzheimer's disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD.<h4>Methods</h4>We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of A?<sub>1-42</sub>, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau<sup>181</sup>) in CSF with INNOTEST enzyme-linked immunosorbent assay.<h4>Results</h4>For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF A?<sub>1-42</sub>, t-Tau, and p-Tau<sup>181</sup> were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/A?<sub>1-42</sub> and -p-Tau<sup>181</sup>/A?<sub>1-42</sub> ratios defined cutoff values at 0.298 and 0.059, respectively.<h4>Conclusions</h4>CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum.
Project description:<h4>Background</h4>Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on ?-amyloid (A?) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans.<h4>Methods</h4>Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n?=?128 with overlapping CSF and A?-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. A?42, A?40, total-tau, and phosphorylated-tau<sub>181</sub> were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with A?-PET, was evaluated.<h4>Results</h4>Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the A?-PET status in a subgroup without CSF (n?=?143), and then when we applied CSF biomarker cutoffs determined based on the A?-PET status, the CSF biomarkers (cutoffs of 642.1?pg/mL for A?42, 0.060 for A?42/A?40, 0.315 for t-tau/A?42, and 0.051 for p-tau/A?42, respectively) showed good agreement with A?-PET (overall AUC ranges of 0.840-0.898). Use of the A?-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (A?42, A?42/A?40, t-tau/A?42, and p-tau/A?42) with overall AUC ranges of 0.876-0.952. During follow-up, participants with AD-like CSF signature determined by A?-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature.<h4>Conclusion</h4>CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with A?-PET in Koreans. The Korean-specific A?-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
Project description:Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (?95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300?mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n?=?1), improved (n?=?2), declined 1-3 points (n?=?5), or declined 4-13 points (n?=?8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r?=?0.97, p?< ?0.0001). CSF [PPX] was not related to CSF [A?(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.
Project description:<h4>Purpose</h4>Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau<sub>181p</sub>) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [<sup>18</sup>F]THK5317 (tau) and [<sup>18</sup>F]FDG PET (glucose metabolism).<h4>Methods</h4>Fourteen Alzheimer's disease (AD) patients (seven prodromal, seven dementia) underwent [<sup>18</sup>F]THK5317 and [<sup>18</sup>F]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included.<h4>Results</h4>While the levels of all forms of CSF tau were found to be inversely associated with baseline [<sup>18</sup>F]FDG uptake, associations with baseline [<sup>18</sup>F]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([<sup>18</sup>F]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau<sub>181p</sub> and T-tau levels, and improved concordance with dichotomized regional [<sup>18</sup>F]THK5317 measures.<h4>Conclusion</h4>Our findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau<sub>181p</sub> and T-tau, tau-368 and tau N-Mid may better capture tau pathology and synaptic impairment.
Project description:<h4>Background</h4>The ability of <sup>18</sup>F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer's disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using <sup>18</sup>F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition.<h4>Methods</h4>Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive <sup>18</sup>F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline <sup>18</sup>F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aβ42/Aβ40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up <sup>18</sup>F-PI-2620 PET scans and cognitive assessments were done in 15 subjects.<h4>Results</h4>Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in <sup>18</sup>F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). <sup>18</sup>F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased <sup>18</sup>F-florbetaben CL in several regions of interest. Elevated <sup>18</sup>F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline.<h4>Conclusions</h4>The findings support the hypothesis that <sup>18</sup>F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in <sup>18</sup>F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of <sup>18</sup>F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents.<h4>Trial registration</h4>Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov ( NCT02956486 ; NCT03036280 ).
Project description:Abstract Introduction We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (A?) and tau measured on the fully automated Lumipulse platform with pre?symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET). Methods In 72 individuals from the Insight 46 study, CSF A?40, A?42, total tau (t?tau), and phosphorylated tau at site 181 (p?tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays, and inter?platform Pearson correlations were derived. Logistic regressions and receiver?operating characteristic analysis generated CSF cut?points optimizing concordance with 18F?florbetapir amyloid PET status (n = 63). Results Measurements of CSF A?, p?tau181, and their ratios correlated well across platforms (r 0.84?.94, P < .0001); those of t?tau and t?tau/A?42 correlated moderately (r 0.57?0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut?points of 0.110 for Lumipulse A?42/A?40, 0.087 for MSD A?42/A?40, and 25.3 for Lumipulse A?42/p?tau181. Discussion The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre?symptomatic AD pathology.
Project description:<h4>Introduction</h4>We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline.<h4>Methods</h4>IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E ε4 allele (<i>APOE</i> ε4) carrier status predicted amyloid beta [Aβ] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253).<h4>Results</h4>Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x <i>APOE4</i> was not related to Aβ chronicity but was significantly associated with CSF phosphorylated tau (P-tau)<sub>181</sub>/Aβ<sub>42</sub> level.<h4>Discussion</h4>In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
Project description:<h4>Purpose</h4>In vivo Alzheimer's disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [<sup>18</sup>F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [<sup>18</sup>F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy.<h4>Methods</h4>We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [<sup>18</sup>F]flortaucipir PET scans were acquired to generate binding potential (BP<sub>ND</sub>) images using receptor parametric mapping and standardized uptake values ratios of 80-100 min (SUVr<sub>80-100min</sub>) post injection. We obtained regional BP<sub>ND</sub> and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only).<h4>Results</h4>Higher [<sup>18</sup>F]flortaucipir BP<sub>ND</sub> was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43-0.46; all p < 0.01). [<sup>18</sup>F]flortaucipir BP<sub>ND</sub> was more strongly associated with cognition and atrophy than CSF p-tau. When [<sup>18</sup>F]flortaucipir BP<sub>ND</sub> and CSF p-tau were entered simultaneously, [<sup>18</sup>F]flortaucipir BP<sub>ND</sub> (range sβ = - 0.20 to - 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BP<sub>ND</sub>.<h4>Conclusion</h4>Regional [<sup>18</sup>F]flortaucipir BP<sub>ND</sub> correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.
Project description:<h4>Objective</h4>To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.<h4>Methods</h4>Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [<sup>11</sup>C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.<h4>Results</h4>Accelerated changes in CSF Aβ<sub>1-42</sub> (Aβ<sub>42</sub>) occurred at 48.28 years of age and in Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ<sub>42</sub> and Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.<h4>Conclusions</h4>Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.