Visual assessment of [18F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

PURPOSE: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR. METHODS: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density. RESULTS: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aß plaque was observed in all FP cases. Regional VR was also associated with regional plaque density. CONCLUSION: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.

Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

PURPOSE: We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer's disease (AD), by using a single dynamic [18F]flortaucipir positron emission tomography (PET) scan. METHODS: Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [18F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BPND) and R1, respectively. (Voxel-wise) linear regressions were used to investigate associations between BPND and/or R1 and cognition. RESULTS: Higher [18F]flortaucipir BPND was associated with lower R1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BPND was associated with worse memory, and higher lateral temporal BPND with worse executive functioning and language. Higher parietal BPND was associated with worse executive functioning, language and attention, and higher occipital BPND with lower cognitive scores across all domains. Higher frontal BPND was associated with worse executive function and attention. For [18F]flortaucipir R1, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R1 with lower language and attention scores. When [18F]flortaucipir BPND and R1 were modelled simultaneously, associations between lower R1 in the lateral temporal ROI  and worse attention remained, as well as for lower parietal R1 and worse executive functioning and attention. CONCLUSION: Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.

Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers.

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([18 F]RO948 in BioFINDER-2, [18 F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aß-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aß-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.

Association of amyloid-ß CSF/PET discordance and tau load 5 years later.

OBJECTIVE: To investigate the association between discordant ß-amyloid (Aß) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later. METHODS: We included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aß42 available. Aß CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aß) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aß CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET- participants who during follow-up (1) progressed to Aß CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET. RESULTS: Aß CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET- (n = 80) participants were overall similar to the CSF-/PET- (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET- group (1.20 ± 0.13) did not differ from CSF-/PET- (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET- participants, 21/64 (33%) progressed to Aß CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET. CONCLUSIONS: Aß load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aß levels on both PET and CSF, the CSF+/PET- group has a distinctly better prognosis.

Amyloid-ß PET and CSF in an autopsy-confirmed cohort.

OBJECTIVE: Accumulation of amyloid-ß is among the earliest changes in Alzheimer's disease (AD). Amyloid-ß positron emission tomography (PET) and Aß42 in cerebrospinal fluid (CSF) both assess amyloid-ß pathology in-vivo, but 10-20% of cases show discordant (CSF+/PET- or CSF-/PET+) results. The neuropathological correspondence with amyloid-ß CSF/PET discordance is unknown. METHODS: We included 21 patients from our tertiary memory clinic who had undergone both CSF Aß42 analysis and amyloid-ß PET, and had neuropathological data available. Amyloid-ß PET and CSF results were compared with neuropathological ABC scores (comprising of Thal (A), Braak (B), and CERAD (C) stage, all ranging from 0 [low] to 3 [high]) and neuropathological diagnosis. RESULTS: Neuropathological diagnosis was AD in 11 (52%) patients. Amyloid-ß PET was positive in all A3, C2, and C3 cases and in one of the two A2 cases. CSF Aß42 was positive in 92% of ≥A2 and 90% of ≥C2 cases. PET and CSF were discordant in three of 21 (14%) cases: CSF+/PET- in a patient with granulomatosis with polyangiitis (A0B0C0), CSF+/PET- in a patient with FTLD-TDP type B (A2B1C1), and CSF-/PET+ in a patient with AD (A3B3C3). Two CSF+/PET+ cases had a non-AD neuropathological diagnosis, that is FTLD-TDP type E (A3B1C1) and adult-onset leukoencephalopathy with axonal spheroids (A1B1C0). INTERPRETATION: Our study demonstrates neuropathological underpinnings of amyloid-ß CSF/PET discordance. Furthermore, amyloid-ß biomarker positivity on both PET and CSF did not invariably result in an AD diagnosis at autopsy, illustrating the importance of considering relevant comorbidities when evaluating amyloid-ß biomarker results.

Why Is Amyloid-ß PET Requested After Performing CSF Biomarkers?

BACKGROUND: Amyloid-ß positron emission tomography (PET) and cerebrospinal fluid (CSF) Aß42 are considered interchangeable for clinical diagnosis of Alzheimer's disease. OBJECTIVE: To explore the clinical reasoning for requesting additional amyloid-ß PET after performing CSF biomarkers. METHODS: We retrospectively identified 72 memory clinic patients who underwent amyloid-ß PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-ß PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-ß PET. RESULTS: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-ß PET scan (n = 53, 74%), followed by incongruent MRI (n = 16, 22%), unusual clinical presentation (n = 11, 15%) and young age (n = 8, 11%). An amyloid-ß PET scan was rarely (n = 5, 7%) requested in patients with a CSF Aß+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n = 11 (15%) cases, the reason that the clinician requested amyloid-ß was not covered by AUC. This happened most often (n = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-ß PET. CONCLUSION: In this single-center study, the main reason for requesting an amyloid-ß PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aß/tau results.

Discordant amyloid-ß PET and CSF biomarkers and its clinical consequences.

BACKGROUND: In vivo, high cerebral amyloid-ß load has been associated with (i) reduced concentrations of Aß42 in cerebrospinal fluid and (ii) increased retention using amyloid-ß positron emission tomography. Although these two amyloid-ß biomarkers generally show good correspondence, ~ 10-20% of cases have discordant results. To assess the consequences of having discordant amyloid-ß PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories. METHODS: We included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer's dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression. RESULTS: We found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = - 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = - 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = - 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (ß [SE] - 0.13[0.08], P = 0.09) and discordant (ß 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (ß - 0.75[0.08] patients (Pinteraction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-ß biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive. CONCLUSIONS: Discordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.

PET and CSF amyloid-ß status are differently predicted by patient features: information from discordant cases.

BACKGROUND: Amyloid-ß PET and CSF Aß42 yield discordant results in 10-20% of memory clinic patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic, and imaging features for amyloid positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-ß status based on PET or CSF or whether this differs by disease stage. METHODS: We included 768 patients (subjective cognitive decline (SCD, n = 194), mild cognitive impairment (MCI, n = 127), dementia (AD and non-AD, n = 447) with amyloid-ß PET and CSF Aß42 measurement within 1 year. Ninety-seven (13%) patients had discordant PET/CSF amyloid-ß status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature and (ii) the patient feature adjusted for the status of the other amyloid modality. RESULTS: APOE4, CSF tau, and p-tau had the highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR = 1.02 [1.01-1.04], pFDR = 0.03), MCI (OR = 1.05 [1.02-1.07], pFDR < 0.01), and dementia (OR = 1.04 [1.03-1.05], pFDR < 0.001), but not for CSF-amyloid. APOE4 (OR = 3.07 [1.33-7.07], punc < 0.01) was associated with CSF-amyloid in SCD, while it was only predictive for PET-amyloid in MCI (OR = 9.44 [2.93, 30.39], pFDR < 0.01). Worse MMSE scores (OR = 1.21 [1.03-1.41], punc = 0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR = 1.17 [1.05-1.31], pFDR = 0.02) only predicted PET positivity in dementia. CONCLUSION: Amyloid status based on either PET or CSF was predicted by different patient features, and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggest that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology.

Assessing Amyloid Pathology in Cognitively Normal Subjects Using 18F-Flutemetamol PET: Comparing Visual Reads and Quantitative Methods.

Our objective was to determine the optimal approach for assessing amyloid disease in a cognitively normal elderly population. Methods: Dynamic 18F-flutemetamol PET scans were acquired using a coffee-break protocol (a 0- to 30-min scan and a 90- to 110-min scan) on 190 cognitively normal elderly individuals (mean age, 70.4 y; 60% female). Parametric images were generated from SUV ratio (SUVr) and nondisplaceable binding potential (BPND) methods, with cerebellar gray matter as a reference region, and were visually assessed by 3 trained readers. Interreader agreement was calculated using κ-statistics, and semiquantitative values were obtained. Global cutoffs were calculated for both SUVr and BPND using a receiver-operating-characteristic analysis and the Youden index. Visual assessment was related to semiquantitative classifications. Results: Interreader agreement in visual assessment was moderate for SUVr (κ = 0.57) and good for BPND images (κ = 0.77). There was discordance between readers for 35 cases (18%) using SUVr and for 15 cases (8%) using BPND, with 9 overlapping cases. For the total cohort, the mean (±SD) SUVr and BPND were 1.33 (±0.21) and 0.16 (±0.12), respectively. Most of the 35 cases (91%) for which SUVr image assessment was discordant between readers were classified as negative based on semiquantitative measurements. Conclusion: The use of parametric BPND images for visual assessment of 18F-flutemetamol in a population with low amyloid burden improves interreader agreement. Implementing semiquantification in addition to visual assessment of SUVr images can reduce false-positive classification in this population.