Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.

BACKGROUND AND OBJECTIVES: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD). METHODS: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology. RESULTS: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs. DISCUSSION: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03518073. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

A review of the flortaucipir literature for positron emission tomography imaging of tau neurofibrillary tangles.

Alzheimer's disease is defined by the presence of ß-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease.

Early tau detection in flortaucipir images: validation in autopsy-confirmed data and implications for disease progression.

BACKGROUND: There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer's disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated. METHODS: A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (ADsignature) (Devous et al., J Nucl Med 59:937-43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944-51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/ADsignature+; Eτ+/ADsignature-; Eτ-/ADsignature-). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/ADsignature- group and B2 NFT scores were created for visual evaluation of uptake. RESULTS: Sixty-four out of 390 analyzable subjects were identified as Eτ+/ADsignature-: 84% were Aß+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/ADsignature- status reflects an early stage of AD, Eτ+/ADsignature- subjects deteriorated significantly faster than Eτ-/ADsignature- subjects, but significantly slower than Eτ+/ADsignature+ subjects, on most measures (i.e., change in ADsignature SUVr, Eτ ROI cortical thickness, and MMSE). The ADsignature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/ADsignature-. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects. CONCLUSION: The Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/ADsignature-) that were primarily Aß+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/ADsignature- subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ-/ADsignature- subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer's disease.

Hemispheric Asymmetry and Atypical Lobar Progression of Alzheimer-Type Tauopathy.

The spread of neurofibrillary tau pathology in Alzheimer disease (AD) mostly follows a stereotypical pattern of topographical progression but atypical patterns associated with interhemispheric asymmetry have been described. Because histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns. Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest in 57 autopsy cases comparing bilateral cortical regions and hemispheres. Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed, whereas marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak Stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and were more frequent in advanced (IV-VI) versus early (I-III) stages. One atypical lobar topographical pattern in which occipital tau pathology density exceeded frontal lobe scores was identified in 4 cases favoring a left dominant asymmetry. We speculate that asymmetry and atypical topographical progression patterns may be associated with atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Relationships Between Cognition and Neuropathological Tau in Alzheimer's Disease Assessed by 18F Flortaucipir PET.

BACKGROUND: Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment. OBJECTIVE: Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains. METHODS: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores. RESULTS: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests. CONCLUSION: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease.

INTRODUCTION: Lanabecestat, a beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)-modifying treatment. As previously reported, amyloid beta (Aß) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported. METHODS: AMARANTH and DAYBREAK-ALZ were 104- and 78-week, multicenter, randomized, double-blind, placebo-controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK-ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK-ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aß neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK-ALZ. Efficacy measures included 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating-Sum of Boxes, Functional Activities Questionnaire, and Mini-Mental State Examination. These studies stopped early due to futility. RESULTS: Despite previously observed annualized reduction in Aß neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK-ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK-ALZ, n = 38) and perfusion (DAYBREAK-ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK-ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment. DISCUSSION: Tau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design.

Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials.

Importance: Flortaucipir positron emission tomography (PET) scans, rated with a novel, US Food and Drug Administration-approved, clinically applicable visual interpretation method, provide valuable information regarding near-term clinical progression of patients with Alzheimer disease (AD) or mild cognitive impairment (MCI). Objective: To evaluate the association between flortaucipir PET visual interpretation and patients' near-term clinical progression. Design/Setting/Participants: Two prospective, open-label, longitudinal studies were conducted from December 2014 to September 2019. Study 1 screened 298 patients and enrolled 160 participants who had a flortaucipir scan at baseline visit. Study 2 selected 205 participants from the AMARANTH trial, which was terminated after futility analysis. Out of the 2218 AMARANTH participants, 424 had a flortaucipir scan around randomization, but 219 did not complete 18-month clinical dementia rating (CDR) assessments and thus were excluded. In both studies, all participants were diagnosed as clinically impaired, and they were longitudinally followed up for approximately 18 months after baseline. Main Outcomes and Measures: Flortaucipir scans were rated as either advanced or nonadvanced AD pattern using a predetermined visual interpretation method. The CDR sum of box (CDR-SB) score was used as primary clinical end point measurement in both studies. Results: Of the 364 study participants who had readable scans, 48% were female (n = 174 of 364), and the mean (SD) age was 71.8 (8.7) years. Two hundred forty participants were rated as having an advanced AD pattern. At 18 months follow-up, 70% of those with an advanced AD pattern (n = 147 of 210) had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. In contrast, only 46% of those with a nonadvanced AD pattern scan (n = 48 of 105) experienced the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; P = .005). The adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (P < .001). Analyses with other clinical end point assessments, as well as analyses with each individual study's data, consistently indicated a higher risk of clinical deterioration associated with an advanced AD scan pattern. Conclusions and Relevance: These results suggest that flortaucipir PET scans, when interpreted with an US Food and Drug Administration-approved, clinically applicable visual interpretation method, may provide valuable information regarding the risk of clinical deterioration over 18 months among patients with AD and MCI. Trial Registration: ClinicalTrials.gov Identifier: NCT02016560 and NCT03901105.

Comparison of regional flortaucipir PET with quantitative tau immunohistochemistry in three subjects with Alzheimer's disease pathology: a clinicopathological study.

BACKGROUND: The objective of this study was to make a quantitative comparison of flortaucipir PET retention with pathological tau and ß-amyloid across a range of brain regions at autopsy. METHODS: Patients with dementia (two with clinical diagnosis of AD, one undetermined), nearing the end of life, underwent 20-min PET, beginning 80 min after an injection of ~370 mBq flortaucipir [18F]. Neocortical, basal ganglia, and limbic tissue samples were obtained bilaterally from 19 regions at autopsy and subject-specific PET regions of interest corresponding to the 19 sampled target tissue regions in each hemisphere were hand drawn on the PET images. SUVr values were calculated for each region using a cerebellar reference region. Abnormally phosphorylated tau (Ptau) and amyloid-ß (Aß) tissue concentrations were measured for each tissue region with an antibody capture assay (Histelide) using AT8 and H31L21 antibodies respectively. RESULTS: The imaging-to-autopsy interval ranged from 4-29 days. All three subjects had intermediate to high levels of AD neuropathologic change at autopsy. Mean cortical SUVr averaged across all three subjects correlated significantly with the Ptau immunoassay (Pearson r = 0.81; p < 0.0001). When Ptau and Aß1-42 were both included in the model, the Ptau correlation with flortaucipir SUVr was preserved but there was no correlation of Aß1-42 with flortaucipir. There was also a modest correlation between limbic (hippocampal/entorhinal and amygdala) flortaucipir SUVr and Ptau (Pearson r = 0.52; p < 0.080). There was no significant correlation between SUVr and Ptau in basal ganglia. CONCLUSIONS: The results of this pilot study support a quantitative relationship between cortical flortaucipir SUVr values and quantitative measures of Ptau at autopsy. Additional research including more cases is needed to confirm the generalizability of these results. Trial registration, NIH Clinicaltrials.gov NCT # 02516046. Registered August 27, 2015. https://clinicaltrials.gov/ct2/show/NCT02516046?term=02516046&draw=2&rank=1.

Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes.

Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants: This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-ß plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

A multicentre longitudinal study of flortaucipir (18F) in normal ageing, mild cognitive impairment and Alzheimer's disease dementia.

The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-ß, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-ß+ and 90 amyloid-ß- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-ß+ but not amyloid-ß- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.

Retrospective assessment of patient characteristics and healthcare costs prior to a diagnosis of Alzheimer's disease in an administrative claims database.

BACKGROUND: The objective of this study was to examine patient characteristics and health care resource utilization (HCRU) in the 36 months prior to a confirmatory diagnosis of Alzheimer's disease (AD) compared to a matched cohort without dementia during the same time interval. METHODS: Patients newly diagnosed with AD (with ≥2 claims) were identified between January 1, 2013 to September 31, 2015, and the date of the second claim for AD was defined as the index date. Patients were enrolled for at least 36 months prior to index date. The AD cohort was matched to a cohort with no AD or dementia codes (1:3) on age, gender, race/ethnicity, and enrollment duration prior to the index date. Descriptive analyses were used to summarize patient characteristics, HCRU, and healthcare costs prior to the confirmatory AD diagnosis. The classification and regression tree analysis and logistic regression were used to identify factors associated with the AD diagnosis. RESULTS: The AD cohort (N = 16,494) had significantly higher comorbidity indices and greater odds of comorbid mental and behavioral diagnoses, including mild cognitive impairment, mood and anxiety disorders, behavioral disturbances, and cerebrovascular disease, heart disease, urinary tract infections, and pneumonia than the matched non-AD or dementia cohort (N = 49,482). During the six-month period before the confirmatory AD diagnosis, AD medication use and diagnosis of mild cognitive impairment, Parkinson's disease, or mood disorder were the strongest predictors of a subsequent confirmatory diagnosis of AD. Greater HCRU and healthcare costs were observed for the AD cohort primarily during the six-month period before the confirmatory AD diagnosis. CONCLUSION: The results of this study demonstrated a higher comorbidity burden and higher costs for patients prior to a diagnosis of AD in comparison to the matched cohort. Several comorbidities were associated with a subsequent diagnosis of AD.

A simulation study comparing slope model with mixed-model repeated measure to assess cognitive data in clinical trials of Alzheimer's disease.

INTRODUCTION: In clinical trials of Alzheimer's disease, a mixed-model repeated measure approach often serves as the primary analysis when evaluating disease progression; a slope model may be secondary. METHODS: Longitudinal change from baseline (14-item version of Alzheimer's Disease Assessment Scale-Cognitive Subscale) was simulated for treatment/placebo from multivariate normal distributions with the variance-covariance matrix estimated from solanezumab trial data. Type I error, power, and bias were based on 18-month treatment contrast. Sample sizes included 500 and 1000 patients/arm. RESULTS: The slope model was more powerful in most scenarios. Mixed-model repeated measure was relatively unbiased in parameter estimation. The slope model yielded unbiased estimates whenever the underlying trajectory was not detectably different from linear. Both methods led to similar type I error. DISCUSSION: In clinical trials of Alzheimer's disease, mixed-model repeated measure analysis with relaxed assumptions on disease progression seems to be preferred. The slope model might be more powerful if the trajectory has little departure from linearity.

Topographic staging of tau positron emission tomography images.

INTRODUCTION: It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. METHODS: Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. RESULTS: All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. DISCUSSION: Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.

Association of Cerebral Amyloid-ß Aggregation With Cognitive Functioning in Persons Without Dementia.

Importance: Cerebral amyloid-ß aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-ß aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.

INTRODUCTION: Performance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials.

INTRODUCTION: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. METHODS: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. RESULTS: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. DISCUSSION: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

The Role of Neuroimaging in the Assessment of the Cognitively Impaired Elderly.

This article reviews the current diagnostic tools that are available for structural, functional, and molecular imaging of the brain, summarizing some of the key findings that have been reported in individuals diagnosed with Alzheimer disease, mild cognitive impairment, prodromal AD, or other prevalent dementias. Given recent advances in the development of amyloid PET tracers, current guidelines for the use of amyloid PET imaging in patients with cognitive complaints are reviewed. In addition, data addressing the potential value of amyloid PET imaging in the clinical setting are highlighted.

Functional limitations and health care resource utilization for individuals with cognitive impairment without dementia: Findings from a United States population-based survey.

INTRODUCTION: Little is known about functional limitations and health care resource utilization of people with cognitive impairment with no dementia (CIND). METHODS: Respondents with stable or progressive cognitive impairment (CI) after the first (index) indication of CIND in 2000-2010 were identified from the Health and Retirement Study (HRS). Respondents never exhibiting CI were identified as potential controls. Propensity score-based optimal matching was used to adjust for differences in demographics and history of stroke. Differences between cohorts were assessed accounting for HRS survey design. RESULTS: After matching, CIND respondents had more functional limitations (difficulty with ≥1 activities of daily living: 24% vs. 15%; ≥1 instrumental activities of daily living: 20% vs. 11%) and hospital stays (37% vs. 27%) than respondents with no CI (all P < .001). Seventy five percent of CIND respondents developed dementia in the observable follow-up (median time: ∼6 years). DISCUSSION: Even before dementia onset, CI is associated with increased likelihood of functional limitations and greater health care resource use.

A Triple Network Connectivity Study of Large-Scale Brain Systems in Cognitively Normal APOE4 Carriers.

The triple network model, consisting of the central executive network (CEN), salience network (SN) and default mode network (DMN), has been recently employed to understand dysfunction in core networks across various disorders. Here we used the triple network model to investigate the large-scale brain networks in cognitively normal apolipoprotein e4 (APOE4) carriers who are at risk of Alzheimer's disease (AD). To explore the functional connectivity for each of the three networks and the effective connectivity among them, we evaluated 17 cognitively normal individuals with a family history of AD and at least one copy of the APOE4 allele and compared the findings to those of 12 individuals who did not carry the APOE4 gene or have a family history of AD, using independent component analysis (ICA) and Bayesian network (BN) approach. Our findings indicated altered within-network connectivity that suggests future cognitive decline risk, and preserved between-network connectivity that may support their current preserved cognition in the cognitively normal APOE4 allele carriers. The study provides novel sights into our understanding of the risk factors for AD and their influence on the triple network model of major psychopathology.