Amyloid Positron Emission Tomography Scan Research Articles

Default mode network tau predicts future clinical decline in atypical early Alzheimer's disease.

Identifying individuals with early-stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau positron emission tomography (PET) in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD. Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16), logopenic variant Primary Progressive Aphasia (n = 15), and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent magnetic resonance imaging (MRI), tau PET, and amyloid PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, Cohen's d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = .30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = .10), tau in other functional networks (R2 = .11-.26), and the magnitude of cortical atrophy (R2 = .20) and amyloid burden (R2 = .09) in the default mode network. Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients one year later. This simple measure could aid the development of a personalized prognostic, monitoring, and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.

The Use of Event Related Potentials to Predict Amyloid PET Status Among Patients from a Memory Disorders Clinic.

Amyloid positron emission tomography (PET) scans provide in vivo evidence of Alzheimer's disease (AD); however, their high cost limits their use in standard clinical care. Event related potentials (ERPs) may represent an inexpensive and non-invasive additional method for detecting AD pathology. We investigated whether ERPs, along with neuropsychological data, serve as predictors of amyloid PET status in patients with memory complaints. Veterans aged 50-100 were recruited from a memory disorders clinic. Participants underwent a neuropsychological battery and an ERP auditory oddball protocol. Twenty-eight patients had a positive amyloid PET scan, and thirty-nine patients had a negative scan. ERP-P200 target amplitude and P200 standard latency were predictors of amyloid PET status. When submitting to ROC analysis, P200 standard latency exhibited the highest specificity and sensitivity in predicting amyloid PET positivity, correctly classifying the amyloid PET status for 86% of patients. ERP-P200 measures are strong indicators of amyloid-β presence in patients from a memory disorder clinic. Increased P200 amplitude and decreased P200 latency in patients with a positive amyloid PET scan may be attributed to hyperactivation of perceptual bottom-up processes compensating for AD-related synaptic loss in the fronto-parietal networks.

Predicting continuous amyloid PET values with CSF tau phosphorylation occupancies.

Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values. CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance. Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids). Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range. Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer's Disease beyond the Cortex.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression.

Practice effects on cognitive testing and amyloid status

AbstractBackgroundPractice effects are improvements in cognitive test scores due to repeated exposure to the same or similar test materials. Reduced practice effects have been reported in older adults with impaired cognition (e.g., Mild Cognitive Impairment, Alzheimer’s disease). However, to our knowledge, practice effects have not been examined in those who are classified as being amyloid positive or negative. Such information could be useful for screening individuals for clinical trials in these conditions.MethodOne hundred fifty‐five older adults with either intact (n = 63) or impaired (n = 92) cognition completed a brief battery of neuropsychological tests twice across one week and an amyloid positron emission tomography (PET) scan. Based on FDA approved prescribing and visual interpretation information, the amyloid PET scan was classified as positive (n = 95) or negative (n = 60). Practice effects across one week were quantified using regression‐based change scores from an independent sample.ResultOn a composite of seven neuropsychological test scores, those who were classified as amyloid positive showed significantly smaller practice effects than those classified as amyloid negative. Similar results were seen on practice effects for 6 of the 7 individuals tests, with smaller practice effects being seen in the amyloid positive participants.ConclusionPractice effects across one week were related to amyloid status in this sample of older adults. As such, these short‐term changes in scores on cognitive tests may be useful for enriching samples for future clinical trials in Alzheimer’s disease.

P205: The effect of APOE e4 genotype on cognition, brain volume, glucose metabolism and amyloid deposition in AD

Objective:Many previous studies have shown that the APOE e4 genotype affects cognition, brain volume, glucose metabolism and amyloid deposition. However, these studies were conducted separately, and few studies simultaneously investigated the effects of the APOE e4 genotype on cognition, brain volume, glucose metabolism and amyloid deposition in Alzheimer disease (AD). The purpose of this study is to simultaneously investigate the association of the APOE e4 genotype with cognition, brain volume, glucose metabolism and amyloid deposition in patients with AD.Methods:This is a cross-sectional study of 69 subjects with Alzheimer’s disease (AD). All subjects were divided into carriers and noncarriers of the ε4 allele. Forty APOE ε4 carriers and 29 APOE ε4 non-carriers underwent neuropsychological, structural magnetic resonance imaging, 18F-fluorodeoxyglucose positron emission tomography scans (18F-FDG-PET) and 18F-Florbetaben amyloid positron emission tomography scans (amyloid PET). Analysis of covariance (ANCOVA) was conducted to compare the differences on cognition, brain volume, glucose metabolism and amyloid deposition between APOE ε4 carriers and non-carriers after controlling demographics.Results:APOE ε4 carriers had 50% lower scores of SVLT_delayed recall compared to non-carriers (0.88 ± 1.65 vs 1.76 ± 1.75). However, APOE ε4 carriers performed better on other cognitive tests than non- carriers (K-BNT (11.04 ± 2.55 vs 9.66 ± 2.82), RCFT (25.73 ± 8.56 vs 20.15 ± 10.82), and Stroop test_color response (48.28 ± 26.33 vs 31.56 ± 27.03)). APOE ε4 carriers had slightly smaller hippocampal volume than non-carriers (3.09 ± 0.38 vs 3.32 ± 0.38), but greater total brain cortical thickness (1.45 ± 1.55 vs 1.37 ± 1.24).Conclusions:We found that APOE e4 genotype is associated with cognition, brain volume in AD, suggesting that APOE e4 genotype can play a very important role in the underlying pathogenesis of AD.

Sensitivity of NIH Toolbox‐Cognition Battery task performance to amyloid positivity status in cognitively normal older adults

AbstractBackgroundAmong cognitively normal older adults, high brain amyloid burden may signal the presence of early Alzheimer’s disease processes. While research has shown subtle neuropsychological performance differences among cognitively intact older adults with and without elevated brain amyloid, early investigation has not found similar between‐group differences on the NIH Toolbox‐Cognition Battery (NIHTB‐CB; Snitz et al., 2020). Here, we utilize data from a longitudinal observational driving study to evaluate potential differences in NIHTB‐CB task performance among older adults determined to be cognitively normal via clinical research consensus, based on brain amyloid status.MethodData from cognitively normal adults age 65+ who completed an amyloid Positron Emission Tomography scan, NIHTB‐CB tasks, and additional neuropsychological testing through the Michigan Alzheimer’s Disease Research Center were analyzed. Amyloid positivity was determined based on a centiloid scale (≤10 indicating amyloid negativity; ≥20 amyloid positivity). Thirty participants were amyloid negative and 17 were amyloid positive. Nine individuals with intermediate amyloid values were excluded. Group differences in NIHTB‐CB performance were analyzed via independent sample t‐tests. Linear regressions were used to assess demographic and NIHTB‐CB task/neuropsychological performance predictors of amyloid positivity.ResultThere were no demographic differences between the groups. Overall, amyloid negative participants outperformed their amyloid positive peers on NIHTB‐CB List Sorting and backward Digit Span tasks (p’s&lt;0.05), both of which are measures of working memory. There were no other group differences in cognitive performance, including episodic memory. The final NIHTB‐CB regression model only included NIHTB List Sorting, which accounted for 16.2% of the variance in amyloid status (F = 8.69, p = 0.005). Digit Span backward similarly accounted for 16.6% of the variance in amyloid status (F = 6.39, p = 0.017).ConclusionAmong cognitively normal older adults with known amyloid status, working memory performance, but not episodic memory performance, differentiated amyloid positive and negative groups. This is consistent with research demonstrating an association between elevated amyloid and executive dysfunction, but not memory impairment, in cognitively normal adults (Tideman et al., 2022). NIHTB‐CB’s List Sorting Working Memory is a complex, challenging sequencing task that appears sensitive to amyloid positivity in older adults and task performance may serve as a marker for early prediction of Alzheimer’s disease.

Assessing the associations between plasma C reactive protein, Ab 42/40 ratio, global amyloid and entorhinal tau PET

AbstractBackgroundLower plasma ratio of amyloid beta (Ab42/Ab40) has been associated with brain amyloid, however, the mechanistic link is unclear. Systemic inflammation may contribute to plasma Ab levels and promote or reduce the accumulation of Alzheimer’s disease (AD) neuropathology. C reactive protein (CRP) is an inflammatory marker implicated in amyloidosis. Using a cross sectional analysis, we evaluated the relationship between blood levels of CRP and Ab ratio, global amyloid positron emission tomography (PET), and tau PET in the entorhinal cortex where tau accumulates early. We hypothesized that Ab positivity would modify the relationship between CRP and AD pathology.MethodIn 969 cognitively normal participants (age: 50‐87, 781 Ab‐/188 Ab+) (Table 1) from the Health and Aging Brain Study‐ Health Disparities (HABS‐HD), we acquired 18F‐PI‐2620 tau‐PET, florbetaben amyloid PET scans, and plasma measures of Ab 42/40 and CRP. Subjects were categorized by Ab + or Ab ‐ by a global amyloid PET standardized uptake value ratio (SUVR) cutoff of 1.08. Within Ab groups, we performed multiple regressions to evaluate associations between 1) global amyloid and entorhinal tau‐PET SUVRs and 2) plasma markers of Ab ratio and CRP. We covaried for age, gender, education, APOE4, and scanner and used false discovery rate (FDR) for multiple comparison corrections.ResultIn Ab+ participants, higher amyloid (b = ‐0.31, p = 0.0005) and tau PET (b = ‐0.36, p = 0.004) were significantly associated with low Ab ratio, but not in Ab‐ for amyloid or tau, with significant interactions by Ab positivity for amyloid (b = ‐0.45, p = 2.65×10−6) and tau (b = ‐0.77, p = 0.0002) (Figure 1). In Ab+ participants, higher CRP was associated with higher Ab ratio (b = 0.21, p = 0.04) and a trend toward lower amyloid (b = ‐0.15, p = 0.084) and tau PET (b = ‐0.22, p = 0.084), but not in Ab‐ participants, with a significant interaction by Ab positivity for Ab ratio (b = 0.46, p = 0.011) (Figure 2) and amyloid (b = ‐0.11, p = 0.0006) and tau PET (b = ‐0.17, p = 0.016).ConclusionIn cognitively intact Ab+ but not Ab‐ adults, higher plasma Ab ratio was associated with lower global amyloid and entorhinal tau PET. In Ab+ participants, higher CRP was associated with blood and brain amyloid and tau levels consistent with less AD pathology.

Prediction of continuous amyloid PET values by CSF tau measures

AbstractBackgroundAlzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden.MethodCSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1).ResultCombining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids).ConclusionCSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures.

Amyloid Positron Emission Tomography and Subsequent Health Care Use Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia

Results of amyloid positron emission tomography (PET) have been shown to change the management of patients with mild cognitive impairment (MCI) or dementia who meet Appropriate Use Criteria (AUC). To determine if amyloid PET is associated with reduced hospitalizations and emergency department (ED) visits over 12 months in patients with MCI or dementia. This nonrandomized controlled trial analyzed participants in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, an open-label, multisite, longitudinal study that enrolled participants between February 2016 and December 2017 and followed up through December 2018. These participants were recruited at 595 clinical sites that provide specialty memory care across the US. Eligible participants were Medicare beneficiaries 65 years or older with a diagnosis of MCI or dementia within the past 24 months who met published AUC for amyloid PET. Each IDEAS study participant was matched to a control Medicare beneficiary who had not undergone amyloid PET. Data analysis was conducted on December 13, 2022. Participants underwent amyloid PET at imaging centers. The primary end points were the proportions of patients with 12-month inpatient hospital admissions and ED visits. One of 4 secondary end points was the rate of hospitalizations and rate of ED visits in participants with positive vs negative amyloid PET results. Health care use was ascertained from Medicare claims data. The 2 cohorts (IDEAS study participants and controls) each comprised 12 684 adults, including 6467 females (51.0%) with a median (IQR) age of 77 (73-81) years. Over 12 months, 24.0% of the IDEAS study participants were hospitalized, compared with 25.1% of the matched control cohort, for a relative reduction of -4.49% (97.5% CI, -9.09% to 0.34%). The 12-month ED visit rates were nearly identical between the 2 cohorts (44.8% in both IDEAS study and control cohorts) for a relative reduction of -0.12% (97.5% CI, -3.19% to 3.05%). Both outcomes fell short of the prespecified effect size of 10% or greater relative reduction. Overall, 1467 of 6848 participants (21.4%) with positive amyloid PET scans were hospitalized within 12 months compared with 1081 of 4209 participants (25.7%) with negative amyloid PET scans (adjusted odds ratio, 0.83; 95% CI, 0.78-0.89). Results of this nonrandomized controlled trial showed that use of amyloid PET was not associated with a significant reduction in 12-month hospitalizations or ED visits. Rates of hospitalization were lower in patients with positive vs negative amyloid PET results.

Sex differences in the structural rich-club connectivity in patients with Alzheimer's disease.

Alzheimer's disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD. In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis. We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia. Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.

Utility of amyloid PET Imaging in a Memory Clinic.

There is greater interest in amyloid biomarker for the diagnosis of Alzheimer disease (AD) with the recent Food and Drug Administration approval of amyloid-targeted therapy. The goal of this study was to assess the clinical utility of amyloid positron emission tomography (PET) in clinically ambiguous cases of cognitive impairment by examining outcomes of patients enrolled in the Imaging Dementia-Evidence of Amyloid Scanning study at 2 academic institutions. Of the 112 patients in the study, 66.1% (n=74) of patients had a positive amyloid PET scan, and 33.96% (n=38) had a negative amyloid PET scan. Lower cognitive test scores were predictive of positive amyloid PET scan ( P =0.001). Eighty-two percent (92/112) of the patients were seen for follow-up. Of the 30 patients with negative amyloid PET scan results, 90% had a diagnosis of non-AD etiology after receiving the negative results, suggesting a negative amyloid scan can be used to rule out AD diagnosis.

187-LB: Preclinical Biomarkers of Alzheimer's Disease Neuropathology in Young Adults with Youth-Onset Diabetes (YDM)—A Proof-of-Concept Study

Adult-onset diabetes increases one's risk for Alzheimer's disease and its related dementias (AD/ADRD). However, little is known about the risk for AD/ADRD in young adults with YDM. The current study quantified preclinical plasma and imaging biomarkers of AD/ADRD in a subset of young adults with YDM from the SEARCH for Diabetes in Youth study cohort (type 1 diabetes [T1D], n=20; type 2 diabetes [T2D], n=21; mean [SD], age=27.4 years [2.2], diabetes duration=13.6 years [2.4], 59% female). Plasma biomarkers were assayed from stored samples at two timepoints: within 1-year of YDM diagnosis (baseline) and in young adulthood via the Quanterix Simoa platform including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), amyloid beta (Aβ)40, and Aβ42. Seven participants from the SEARCH subset (T1D=6, T2D=1; age=30.7 years [2.4], 87% female) and four age-similar controls (age=26.5 years [4.4], 50% female) underwent [18F]PI-2620 tau positron emission tomography (PET) to quantify brain tau density. Tau standardized uptake value ratios (SUVRs) with partial volume correction were derived in AD/ADRD sensitive brain regions. From baseline to young adulthood, plasma pTau181 significantly increased in both YDM-T1D and YDM-T2D (mean change=9.5 pg/mL [3.8] and 12.4 pg/mL [6.3], respectively; p&amp;lt;0.001). Average tau SUVRs in the middle temporal poles (SUVR=1.26 [0.14] vs 1.17 [0.04]) and parahippocampal gyri (SUVR=1.01 [0.33] vs 0.92 [0.05]) were greater in YDM vs. controls. However, these differences were not statistically significant. Our preliminary results suggest that YDM may increase the risk of AD/ADRD via accelerated accumulation of soluble phosphorylated tau. Additional measurement of AD/ADRD neuropathology, including amyloid PET scans, is currently underway to further understand the trajectory of preclinical AD/ADRD pathology in YDM. Disclosure A. Shapiro: None. K. K. Harrall: None. R. A. Barcus: None. J. Tan: None. B. Bettcher: None. A. Thaker: None. K. A. Walker: None. A. D. Liese: None. D. Dabelea: None. C. T. Whitlow: Consultant; Biogen, Genentech, Inc. C. Coughlan: None. J. Kim: None. H. Potter: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. M. E. Pauley: None. B. S. Rajic: None. J. Truong: None. D. H. Glueck: None. Funding American College of Radiology

Immunity gene IFITM3 variant: relation to cognition and Alzheimer pathology

AbstractBackgroundIFITM3, an innate immune response protein and inhibitor of viral infection, was reported to modulate amyloid‐β production in Alzheimer’s disease (AD). We aimed to identify single‐nucleotide polymorphisms (SNPs) in IFITM3 associated with cognition and AD biomarkers.MethodWe used genetic, longitudinal cognition and AD biomarker data from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. First, we performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance. Second, we performed SNP‐based association analysis in IFITM3 with cognitive decline and AD biomarkers from amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI).ResultGene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance (permutation‐corrected p = 1.25×10−3). Particularly, among two SNPs (rs10751647, rs2091850) in IFITM3 significantly associated with cognitive performance, rs10751647 was associated with cognitive decline in ADNI, which was replicated in AddNeuroMed. In addition, rs10751647 was significantly associated with amyloid‐β deposition measured by amyloid PET scan, CSF phosphorylated tau levels, and entorhinal cortical thickness measured by MRI scan in ADNI. The association of rs10751647 with entorhinal cortical thickness was replicated in AddNeuroMed. Participants with minor alleles (C) of rs10751647 have less cognitive decline, less amyloid and tau burden, and less brain atrophy. eQTL analysis showed that rs10751647 is associated with IFITM3 expression levels in blood and brain.ConclusionThis suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immune activity and infection in AD.

Change in the Quick Dementia Rating System Across Time in Older Adults with and without Cognitive Impairment.

The Quick Dementia Rating System (QDRS) is a brief, informant-reported dementia staging tool that approximates scores on the Clinical Dementia Rating Scale in patients with Alzheimer's disease (AD). The current study sought to examine change in the QDRS across time, which is necessary for clinical and research efforts. One-hundred ten older adults (intact, mild cognitive impairment [MCI], mild AD, classified with Alzheimer's Disease Neuroimaging Initiative criteria) were rated on the QDRS by an informant and had an amyloid positron emission tomography scan at baseline. The informant re-rated each participant on the QDRS after one year. Dependent t-tests compared the entire sample and various subgroups (e.g., cognitive status, amyloid status) on baseline and follow-up QDRS scores. In the entire sample, the Total score on the QDRS significantly increased (i.e., worsened) on follow-up (p < 0.001). When subgroups were analyzed, the MCI and mild AD subjects showed increasing (i.e., worsening) QDRS Total scores (both p < 0.001), but the intact subjects remained stable over time (p = 0.28). Additionally, those classified as being amyloid positive at baseline showed significantly increased QDRS Total scores at follow-up (p < 0.001) compared to those who were amyloid negative at baseline, whose QDRS Total scores remained stable over time (p = 0.63). The QDRS can potentially demonstrate worsening functioning status across one year, especially in those who have MCI or mild AD and those who are amyloid positive. Therefore, the current results preliminarily suggest that the QDRS may provide an efficient tool for tracking progression in clinical trials in AD.

Correlation of 18F-PM-PBB3 (18F-florzolotau) Tau PET Imaging with Postmortem Neuropathological Findings in A Case with Progressive Supranuclear Palsy (P9-11.015)

<h3>Objective:</h3> To examine correlations between <i>in vivo</i> positron emission tomography (PET) imaging with 18F-PM-PBB3 (18F-florzolotau) and postmortem neuropathological findings in a patient with progressive supranuclear palsy (PSP). <h3>Background:</h3> There have been no reports demonstrating tight PET-pathology associations in the same individual with non-Alzheimer-type neurodegenerative disorders, including PSP, characterized by aggregations of four-repeat tau isoforms only. 18F-florzolotau is a PET probe allowing high-contrast imaging of Alzheimer’s and non-Alzheimer tau pathologies irrespective of isoform compositions, while the utility of this tracer for quantifying the abundance of tau deposits in living cases is yet to be verified. <h3>Design/Methods:</h3> <h3>Patient:</h3> A 65-year-old male with a clinical diagnosis of PSP Richardson syndrome underwent 11C-PiB amyloid and 18F-florzolotau tau PET scans one year before autopsy. Clinical, neuroimaging, and neuropathological findings in this case were briefly summarized elsewhere (K Tagai, et al. Neuron 2021). <h3>Image analysis:</h3> The standardized uptake value ratio (SUVR) image was generated from averaged PET images at 90–110 min after injecting 18F-florzolotau. The reference region was determined using an optimized reference tissue method (K Tagai, et al. medRxiv DOI: https://doi.org/10.1101/2022.02.13.22270135). <h3>Neuropathological analysis:</h3> Quantitative analysis of tau burden was performed using an anti-phosphorylated tau antibody (AT8). A threshold-based binarization method was used for determining the mean AT-8-positive area (%area tau burden). <h3>Results:</h3> 18F-florzolotau PET showed enhanced radiosignals in the brainstem, subthalamic nucleus, and basal ganglia, and the presence of PSP-characteristic tau deposits, including the globose neurofibrillary tangle, tufted astrocytes and coiled bodies, primarily in these areas was confirmed by neuropathological assays. There was a close correlation between regional radioprobe SUVR and %area tau burden (<i>r</i><i>_s</i> = 0.63, <i>p</i> &lt;0.0001). Amyloid PET was negative by visual read. <h3>Conclusions:</h3> 18F-florzolotau PET measures reflect the abundance of tau pathologies in PSP. <b>Disclosure:</b> Dr. Endo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for APRINOIA Therapeutics. Dr. Endo has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AbbVie Inc.. The institution of Dr. Endo has received research support from JSPS KAKENHI 21K15705. Dr. Araki has nothing to disclose. Dr. Takeda has nothing to disclose. Dr. Takado has nothing to disclose. Dr. Tagai has nothing to disclose. Dr. Matsuoka has nothing to disclose. Dr. Seki has nothing to disclose. Dr. Takahata has nothing to disclose. Dr. Sahara has nothing to disclose. Hitoshi Shinotoh has nothing to disclose. Mr. Kawamura has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Honda has nothing to disclose. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for eli lilly. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical . Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Nihon Medi-Physics. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for FUJIFILM Toyama Chemical. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunplanet . Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NIPPON CHEMIPHAR. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sumitomo Pharma. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GE Healthcare. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for CHUGAI PHARMACEUTICAL. Prof. SHIMADA has received intellectual property interests from a discovery or technology relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. The institution of Dr. Higuchi has received research support from APRINOIA Therapeutics.

Change on the Repeatable Battery for the Assessment of Neuropsychological Status and its relationship to brain amyloid

ABSTRACT Background The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer’s disease (AD), including brain amyloid plaque density. However, less is known about if changes in the RBANS across time are also related to brain amyloid deposition. The current study sought to expand on prior work by examining the relationship between changes over time on the RBANS and amyloid deposition via positron emission tomography (PET). Method One-hundred twenty-six older adults with intact or impaired cognition and daily functioning underwent repeat assessment with the RBANS across nearly 16 months, as well as had a baseline amyloid PET scan. Results In the entire sample, amyloid deposition was significantly related to change on all five Indexes and the Total Scale score of the RBANS, with greater amyloid being associated with worsening cognition. This pattern was also observed in 11 of 12 subtests. Conclusions Whereas prior studies have identified a relationship between baseline RBANS and amyloid status, the current findings support that changes in the RBANS are also indicative of AD brain pathology, even if these findings are mediated by cognitive status. Although replication in a more diverse sample is needed, these results continue to support the use of the RBANS in AD clinical trials.

Lecanemab for Alzheimer's disease: new hope or another false dawn?

Lecanemab for Alzheimer's disease: new hope or another false dawn?

Diagnostic Performance of a Tablet Computer-Based Cognitive Screening Test for Identification of Amnestic Mild Cognitive Impairment.

Early and appropriate diagnosis of amnestic mild cognitive impairment (aMCI) is clinically important because aMCI is considered the prodromal stage of dementia caused by Alzheimer's disease (AD). aMCI is assessed using the comprehensive neuropsychological (NP) battery, but it is rater-dependent and does not provide quick results. Thus, we investigated the performance of the computerized cognitive screening test (Inbrain Cognitive Screening Test; Inbrain CST) in the diagnosis of aMCI and compared its performance to that of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test (CERAD-K), a comprehensive and pencil-and-paper NP test. A total of 166 participants were included in this cross-sectional study. The participants were recruited as part of a prospective, community-based cohort study for MCI (PREcision medicine platform for mild cognitive impairment on multi-omics, imaging, evidence-based R&amp;BD; PREMIER). All participants were assessed using the CERAD-K and the Inbrain CST. The Inbrain CST comprised seven subtests that assessed the following five cognitive domains: attention, language, visuospatial, memory, and executive functions. Seventy-six participants underwent brain magnetic resonance imaging and [18F]-flutemetamol positron emission tomography (PET). We evaluated the diagnostic performance of the Inbrain CST for the identification of aMCI by comparing the findings with those of CERAD-K. We also determined the characteristics of aMCI patients as defined by the CERAD-K and Inbrain CST. Of the 166 participants, 93 were diagnosed with aMCI, while 73 were cognitively unimpaired. The sensitivity of the Inbrain CST for aMCI diagnosis was 81.7%, and its specificity was 84.9%. Positive and negative predictive values were 87.4% and 78.5%, respectively. The diagnostic accuracy was 83.1%, and the error rate was 16.9%. Demographic and clinical characteristics between individuals with aMCI defined by the Inbrain CST and CERAD-K were not significantly different. The frequency of positive amyloid PET scan, the hippocampal/parahippocampal volumes, and AD signature cortical thickness did not differ between the patients with aMCI defined by CERAD-K and those with aMCI defined by the Inbrain CST. The Inbrain CST showed sufficient sensitivity, specificity, and positive and negative predictive values for diagnosing objective memory impairment in aMCI. In addition, aMCI patients identified by CERAD-K and the Inbrain CST showed comparable clinical and neuroimaging characteristics. Therefore, the Inbrain CST can be considered an alternative test to supplement the limitations of existing pencil-and-paper NP tests.

18F‐fluorodeoxyglucose‐positron emission tomography Findings in Patients with Genetic Frontotemporal Dementia

AbstractBackgroundMutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls.Methods(18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient’s FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference.ResultOn review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1).On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2).ConclusionHypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes.