The spread of paired helical filaments (PHF) tau in the brain is currently under investigation. Different groups suggest tau could be either propagating from a seed or an imbalance in local production and clearance that leads to increased deposition. Studies have used resting state fMRI with tau PET to understand the spread of tau in humans. In this study, we introduce a new subject-based measure of tau PET connectivity that describes the spread of tau using only Flortaucipir (FTP) PET images. Here we demonstrate how FTP PET network measurements of tau spread differentiates probable Alzheimer's dementia (pAD), mild cognitive impairment (MCI), and cognitively unimpaired (CU) study participants from the Alzheimer's Disease NeuroImaging Initiative (ADNI), and suggest its promise to detect differences in network measures in CU persons at genetic risk for AD. We determined a FTP network for each subject using a method from graph theory. From the undirected weighted graph created from the inter-regional distances, the global and local (efficiency, network strength) measurements of spread of tau in the network were calculated. Next, we compared our measurements to SUVR in common regions such as prespecified ROIs (entorhinal, parahippocampal, inferior temporal, precuneus) as well as mean cortical region from Mayo and partial volume corrected (PVC) SUVR BraakI-II, BraakIII-IV, and BraakV-VI from Berkeley in their ability to distinguish 15 pAD, 63 MCI, and 81 CU research participants from one another. Finally, we compared these novel and established measurements in their ability to distinguish in CU 49 APOE4 carriers from 24 non-carriers. Like several of the established ROI flortaucipir PET measurements, each of the global and several of the local flortaucipir connectivity measurements were significantly different in the three subject groups (pAD>MCI>CU, p
Abstract Background APOE 4 gene dose, the number of apolipoprotein E ‐ɛ4 ( APOE 4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and measurements of core AD CSF biomarkers in APOE 4 gene dose. Here, we characterize longitudinal neurofilament light chain (NfL) changes in the Arizona APOE cohort, including cognitively unimpaired participants, with longitudinal plasma NfL measurements in APOE 4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs). Method Plasma NfL measurements were performed at the University of Gothenburg using a Single molecule array (Simoa) immunoassay. Annual log‐transformed plasma NfL changes were compared with linear‐tend and univariate ANOVA adjusted for age, sex, and education in 45 HMs, 107 HTs, and 201 NCs who were cognitively unimpaired, 47‐85 years old and did not differ significantly in their age, sex, or educational level. Pearson r correlations with age and annual log‐transformed NfL changes were assessed in 353 participants with at least 2 visits (range 2‐6 visits with an average of ∼3) and an average follow‐up of ∼7 years (range 1‐12 years). Result Annual log‐transformed NfL changes were linearly associated with APOE 4 gene dose (linear trend HM>HT>NC, P=0.01) and positively associated with age (r = 0.31, P<0.0001). Pairwise comparisons from the univariate ANOVA adjusted for age, sex, and education (P=0.001) showed significantly higher annual NfL changes in HM and HT groups versus NC controls (P=0.01). Conclusion Age and APOE 4 gene dose are associated with greater annual plasma NfL changes in CU subjects close to their estimated ages at clinical onset. Studies are needed to better elucidate relationships between different Aβ, tau, inflammatory, and other CSF, or blood‐based biomarkers, and APOE 4 gene dose at other ages and in larger subject groups.
Abstract Background In contrast to late onset Alzheimer’s disease (LOAD), the late clinical stages of autosomal dominant Alzheimer’s disease (ADAD) are associated with greater neuropathological evidence of cerebellar amyloid plaque (Aß) deposition. In this study, we used PET measurements of fibrillar Aß burden to characterize the presence and age at onset of cerebellar Aß deposition in cognitively unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD. Method Florbetapir and PiB PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and the Colombia‐Boston (COLBOS) longitudinal biomarker study were included. Template‐based cerebellar standard uptake value ratios (SUVR), using a known‐to‐be‐spared pontine reference region, were used to 1) compare 290 cognitively unimpaired 28‐56 year‐old mutation carriers and non‐carriers; 2) characterize associations among cerebellar‐to‐pontine SUVR and age, mean cortical SUVRs, and episodic memory performance; and 3) estimate the age at which cerebellar‐to‐pontine SUVRs begins to differ significantly in the carrier and non‐carrier groups. Result Compared to non‐carriers, cognitively unimpaired carriers had higher cerebellar‐to‐pontine florbetapir and PiB SUVRs ( p <.0001). Mean cortical SUVRs were positively correlated with age and negatively correlated with episodic memory performance ( p <.05). SUVRs began to distinguish carriers from non‐carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Conclusion This PET study provides evidence of cerebellar Aß plaque deposition in cognitively unimpaired mutation carriers starting years before their clinical onset. Additional studies are needed to clarify the impact of using a cerebellar versus pontine reference region on the power to detect and track ADAD progression, even in preclinical stages of this disorder.
In the next few years, several Alzheimer's disease (AD) trials have a chance to clarify which biomarker endpoints are reasonably likely to predict a treatment's clinical benefit, such that those biomarker endpoints could help to find and support the accelerated approval of effective AD prevention therapies in cognitively unimpaired at-risk persons as soon as possible. We used data from the AD Neuroimaging Initiative (ADNI) to estimate the number of unimpaired amyloid-β (Aβ)-positive older adults, including those with or without at least one APOE4 allele, needed to evaluate an AD prevention therapy in 24-month placebo-controlled trials using several biomarker endpoints. Baseline and approximately 24-mo follow-up florbetapir PET, FDG PET and structural MRI data were used to estimate the respective number of cognitively unimpaired 65–80 year-old Aβ-positive trial completers, including those with or without at least one APOE4 allele, needed to detect a 25% treatment effect in 24-mo AD prevention trials with 80% power and two-tailed P=0.05. Aβ positivity was defined as a baseline florbetapir standard uptake value ratio (SUVR) ≥1.18, PiB SUVR ≥ 1.47, or CSF Aβ42 level ≤ 192 pg/mL. We estimate that approximately 159, 183, 273, and 820 Aβ-positive trial completers per group, 94, 128, 254, and 457 Aβ-positive APOE4 carrier completers per group, or 190, 247, 286, and 1,483 Aβ-positive APOE4 non-carrier completers per group are needed for the respective detection of 25% treatment effects on cerebral-to-white matter florbetapir SUVR increases (in the absence of SUVR-reversing effects), Iterative Principal Component Analysis (IPCA)-based whole brain volume declines, FreeSurfer-based hippocampal volumes declines, and FDG PET declines in an AD-related statistical region-of-interest (sROI) in 24-month placebo-controlled AD prevention trials. We have begun to estimate the number of cognitively unimpaired at-risk participants needed to evaluate AD prevention therapies in a 24-month trial using biomarker endpoints. These trials may provide the best chance to find and support the approval and widespread availability of effective AD prevention therapies by 2025. Planning for a potential trial is underway.
While brain imaging and cerebrospinal fluid (CSF) biomarkers have been used in the early detection and tracking of Alzheimer's disease (AD), their ability to predict subsequent clinical decline remains to be defined. In this study, we compared the ability of baseline PET amyloid-β (Aβ) and CSF measurements to predict subsequent cognitive decline in unimpaired Presenilin-1 (PSEN1) E280A mutation carriers from the Colombian autosomal dominant AD (ADAD) kindred, up to almost 25 years before the kindred's estimated median age of 44 at the onset of mild cognitive impairment. Thirty-seven cognitively unimpaired mutation carriers and non-carriers, aged 20-44 years, were recruited from the Alzheimer's Prevention Initiative (API) Colombia Registry. Baseline cerebral-to-cerebellar florbetapir PET standard-uptake-value ratios (SUVRs) and CSF Aβ1-42, total-tau and phospho-tau181 levels were related to 2-3 year subsequent decline on the API preclinical ADAD composite cognitive test score, previously found to be associated with preclinical progression. The mixed random effect model was used to estimate the relationship between baseline measures and subsequent cognitive decline in the mutation carriers. In an independent replication, 2-3 year decline on the composite cognitive test score distinguished between carriers and non-carriers (p=0.03). In the carrier group, baseline florbetapir SUVRs and CSF p-tau/Aβ1-42 ratios were associated with subsequent decline on the composite cognitive test score (p=0.008, 0.04, respectively). CSF Aβ1-42, total tau, and p-tau levels alone were not (p= 0.19, 0.43 and 0.88, respectively), even after adjusting for age. Florbetapir SUVRs were slightly but not significantly better than CSF p-tau/Aβ1-42 ratios (p=0.09), and better than CSF Aβ1-42, total tau, and p-tau levels (p= 0.04, 0.04, and 0.06, respectively) in predicting subsequent cognitive decline. Aβ PET and, to a lesser extent, CSF p-tau/Aβ1-42 measurements may provide prognostic indicators of AD-related cognitive decline in ADAD mutation carriers. Indeed, Aβ PET may be a better prognostic indicator than CSF Aβ and tau levels in the group of mutation carriers assessed up to 25 years before their estimated age at clinical onset. Research is needed to further clarify the prognostic value of these biomarkers in cognitively unimpaired persons at risk for autosomal dominant and late-onset AD.
Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players.Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs).Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions.Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
We previously characterized associations between the magnitude and spatial extent of amyloid-β(Aβ) PET measurements and apolipoprotein E (APOE4) gene dose, reflecting three levels of genetic risk for late-onset Alzheimer's disease(AD), in cognitively unimpaired late-middle-aged research volunteers (Reiman, 2009). In this study, we sought to characterize the relationships between regional tau PET measurements and APOE4 gene dose in cognitively unimpaired late middle-aged and older adults, along with the extent to which these associations are influenced by age, long-term verbal memory, and presence or absence of a positive Aβ PET scan. Flortaucipir (FTP) and PiB PET scans were used for the respective measurement of paired helical filament(PHF) tau and fibrillar Aβ burden in 138 cognitively unimpaired 63±8.2(range 47-86) y/o participants in the Arizona APOE Cohort Study and the Mayo Clinic Study of Aging, including 25 APOE4 homozygotes(HM), 37 heterozygotes(HT), and 76 non-carriers(NC) who were matched for age, sex, and educational level. Aβ-positivity was defined by a cerebral-to-cerebellar PiB SUVR≥1.42. Cerebral-to-cerebellar FTP SUVRs were computed in pre-specified entorhinal cortex(ERC) and inferior temporal cortex (ITC) regions-of-interest(ROIs). Relationships with age were adjusted for study site, sex and education; relationships with AVLT long-term recall were also adjusted for age. 7(28%), 10(29%), and 5(7%) of the HM, HT, and NC were PiB+. There was a significant association between APOE4 gene dose and FTP SUVRs in ERC (linear-trend, HM>HT>NC, P=0.02) but not in ITC (P=0.92). The associations between APOE4 gene dose and ERC SUVRs were not significant in those who were PiB+ (P=0.15), or in those who were PiB- (P=0.42). There were significant associations between age and FTP SUVRs in aggregate PiB- and PiB+ HT and HM in ITC (p=0.01, 0.00) and ERC for HT (p=0.02). The association in the ITC persisted in PiB- HM (p=0.04) and not significant in PiB- HT (p=0.08). There were no associations between AVLT delayed recall and FTP SUVRs. It is possible that significant correlations in PiB+ groups were not seen due to small sample size. This study provides new information about PHF tau PET measurements and their relationships with age and memory decline in APOE4 HM, HT and NC.
Degeneration of the serotonin system has been observed in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). In transgenic amyloid mouse models, serotonin degeneration is detected prior to widespread cortical beta-amyloid (Aβ) deposition, also suggesting that serotonin degeneration may be observed in preclinical AD. The differences in the distribution of serotonin degeneration (reflected by the loss of the serotonin transporter, 5-HTT) relative to Aβ deposition was measured with positron emission tomography in a group of individuals with MCI and a group of healthy older adults. A multi-modal partial least squares (mmPLS) algorithm was applied to identify the spatial covariance pattern between 5-HTT availability and Aβ deposition. Forty-five individuals with MCI and 35 healthy older adults were studied, 22 and 27 of whom were included in the analyses who were "amyloid positive" and "amyloid negative", respectively. A pattern of lower cortical, subcortical and limbic 5-HTT availability and higher cortical Aβ deposition distinguished the MCI from the healthy older control participants. Greater expression of this pattern was correlated with greater deficits in memory and executive function in the MCI group, not in the control group. A spatial covariance pattern of lower 5-HTT availability and Aβ deposition was observed to a greater extent in an MCI group relative to a control group and was associated with cognitive impairment in the MCI group. The results support the application of mmPLS to understand the neurochemical changes associated with Aβ deposition in the course of preclinical AD.
