Negative Amyloid PET Research Articles

Significance of a positive tau PET scan with a negative amyloid PET scan.

The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A-. We evaluated 98 participants from the Mayo Clinic who were T+ and A-. Participants were matched 2:1 to A- and T- cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. The A-T+ group demonstrated lower performance than the A-T- group on the Mini-Mental Status Exam (MMSE) (p<0.001), Wechsler Memory Scale-Revised Logical Memory I (p<0.001) and Logical Memory II (p<0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p=0.004), category fluency (animals p=0.005; vegetables p=0.021), Trail Making Test A and B (p<0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A-T+ and CI A-T+. A-T+ participants show an association with lower cognitive performance.

Probable 4-Repeat Tauopathy Criteria Predict Brain Amyloid Negativity, Distinct Clinical Features, and FDG-PET/MRI Neurodegeneneration Patterns in Corticobasal Syndrome.

Corticobasal syndrome (CBS) is associated with diverse underlying pathologies, including the four-repeat (4R)-tauopathies. The Movement Disorders Society (MDS) criteria for progressive supranuclear palsy (PSP) proposed the novel category "probable 4R-tauopathy" to address the phenotypic overlap between PSP and corticobasal degeneration (CBD). To investigate the clinical ability of the MDS-PSP criteria for probable 4R-tauopathy in predicting a negative amyloid-PET in CBS. Additionally, this study aims to explore CBS patients classified as 4R-tauopathy concerning their clinical features and neuroimaging degeneration patterns. Thirty-two patients with probable CBS were prospectively evaluated and split into those who fulfilled or did not fulfill the 4R-tauopathy criteria (CBS-4RT+ vs. CBS-4RT-). All patients underwent positron emission tomographies (PET) with [18 F]fluorodeoxyglucose and [11 C]Pittsburgh Compound-B (PIB) on a hybrid PET-MRI scanner to perform multimodal quantitative comparisons with a control group. Eleven patients were clinically classified as CBS-4RT+, and only one had a positive PIB-PET. The CBS-4RT+ classification had 92% specificity, 52% sensitivity, and 69% accuracy in predicting a negative PIB-PET. The CBS-4RT+ group presented with dysarthria and perseveration more often than the CBS-4RT- group. Moreover, the CBS-4RT+ group showed a prominent frontal hypometabolism extending to the supplementary motor area and striatum, and brain atrophy at the anterior cingulate and bilateral striata. The 4R-tauopathy criteria were highly specific in predicting a negative amyloid-PET in CBS. Patients classified as 4R-tauopathy presented distinct clinical aspects, as well as brain metabolism and atrophy patterns previously associated with tauopathies.

The use of Event Related Potentials to predict amyloid PET status among patients from a memory disorders clinic

AbstractBackgroundAmyloid PET scans provide in vivo evidence of Alzheimer’s Disease (AD) however, due to high cost and limited insurance coverage, they are not available as part of standard clinical care. Event Related Potentials (ERPs) are inexpensive, and non‐invasive method to directly measure brain physiology that may allow an alternative method for detection of AD pathology.MethodWe investigated whether ERPs together with neuropsychological data are predictors of amyloid PET status in patients with memory complaints. Older veterans aged 50‐100 were recruited from a memory disorders clinic at VA Boston Healthcare System. Participants underwent a standard neuropsychological battery and an ERP auditory oddball protocol. Twenty‐eight patients had a positive amyloid PET scan, and thirty‐nine patients had a negative amyloid PET scan.ResultsTwo neuropsychological measures (CERAD Delayed Recall and MMSE) were predictors of amyloid PET status. Increased P200 target amplitude (Figure 1B), and decreased P200 standard latency (Figure 1A) in patients with amyloid PET positive scan were found. ERP‐P200 amplitude in response to target tones and ERP‐P200 latency in response to standard tones were also predictors of amyloid PET status. The highest classification accuracy was obtained when combining CERAD Delayed Recall, MMSE and ERP‐P200 standard latency.ConclusionERP‐P200, especially when combined with cognitive measures of delayed memory and overall cognitive function, was predictive of amyloid beta (Aβ) load in the brain of patients from a memory disorder clinic. Increased P200 amplitude, and decreased P200 latency in patients with amyloid PET positive scan might suggest hyperactivation of perceptual bottom‐up processes to compensate for AD‐related synaptic loss in the fronto‐parietal networks.

Measurement of amyloid beta in nasal secretions as a potential biomarker for Alzheimer’s disease

AbstractBackgroundWe investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease using multichannel impedance analyzer (ToAD) and electrical‐immunosorbent assay (El‐ISA), and determined the predictive value of Aβ in nasal secretions for AD diagnosis.MethodNasal secretions were obtained from 84 participants with probable AD dementia (ADD), 83 with amnestic mild cognitive impairment (MCI), 22 with cognitive decline associated with other neurological disorders (OND), and 62 cognitively unimpaired (CU) participants. Aβ oligomers in nasal secretions were analyzed using ToAD / El‐ISA analytical systems. Capture antibodies in El‐ISA kits specifically capture Aβ oligomer in nasal secretion, and then detection probes for El‐ISA method bind with amyloid beta oligomer sequentially. Finally, unbound free detection probes in solution was electrochemically measured by ToAD analyzer for quantifying Aβ oligomers. Because this analytical method is based on the back‐titration, the change of electrical signal is inversely proportional with the concentration of detectable Aβ oligomers. Electrical signals finally expressed to Cantis AD Index (CAI, 0∼99) which normalized by standards for system calibration.ResultThe CAI was higher in the probable ADD group than in the CU group (p &lt; 0.05). The accuracy of the CAI was fair in separating into the probable ADD and CU groups (AUC of the ROC curve = 0.665, 95% CI = 0.572‐0.758, SE = 0.047, p = 0.001). The accuracy of the CAI was fair in separating into the participants with positive amyloid PET scan and those with negative amyloid PET scan (area under curve [AUC] of the receiver operating characteristic [ROC] curve = 0.697, 95% confidence interval [CI] = 0.629‐0.766, SE = 0.035, p &lt; 0.001). The CAI has a negative correlation with Mini‐Mental State Examination score and positive correlations with Clinical Dementia Rating scale‐Sum of Boxes and amyloid PET centiloid scale scores.ConclusionThese results demonstrate that the level of Aβ in nasal secretions increases in AD and the detection of Aβ in nasal secretions using ToAD / El‐ISA analytical systems may be possible in predicting ADD.

Significance of a positive tau pet scan with a negative amyloid pet scan

AbstractBackgroundThe implications of a positive tau (T) Positron Emission Tomography (PET) with a negative beta amyloid (A) PET are not well understood. We investigated cognitive performance in participants who were positive on tau PET but negative on beta amyloid PET.MethodWe evaluated 98 participants from the Mayo Clinic Study of Aging (MCSA) and the Mayo Clinic Alzheimer’s Disease Research Center (ADRC) who were positive for Flortaucipir (FTP) and negative for PiB PET. Participants were classified as A‐ and T+ based on Standardized Uptake Value Ratios (SUVr) of FTP and PiB PET scans, and were matched 2:1 to amyloid negative and tau negative cognitively unimpaired controls from the MCSA. Cognitive test scores were compared between the combined ADRC/MCSA group and MCSA only group. We also examined clinical diagnoses in our cohort. The most common were Alzheimer’s Disease, mild cognitive impairment (MCI), Dementia with Lewy Bodies (DLB) and Frontotemporal dementia (FTD) amongst others.ResultThere were no significant differences in demographic features or PiB SUVr between groups. There were significant differences in APOE genotype between groups. In the combined ADRC/MCSA group, 25% of A‐T‐ and 13% of A‐T+ were APOE e4 carriers (p = 0.016), and in the MCSA only group, 27% of A‐T‐and 10% of A‐T+ were APOE e4 carriers (p = 0.010). In the combined ADRC/MCSA group, the A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini Mental Status Exam (MMSE) (p&lt;0.001), Wechsler Memory Scale‐Revised Logical Memory I (p&lt;0.001) and Logical Memory II (p&lt;0.001), Auditory verbal Learning Test Delayed Recall (AVLT) (p = 0.004), Category fluency animals (p = 0.005), Category fluency vegetables (p = 0.021), Trailmaking test A (p&lt;0.001), Trail making test B (p&lt;0.001), Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) (p = 0.002), and Unified Parkinson’s Disease Rating Scale part III (UPDRS III) (p = 0.003). In the MCSA only group, the A‐T+ group had lower scores on Logical Memory II (p = 0.022), AVLT delated recall (p = 0.04), and WAIS‐R block design (p = 0.035) compared to the A‐T‐group.ConclusionPositive tau PET in the absence of beta‐amyloid positivity is associated with lower cognitive performance.

57 Clinical Utility of Neuropsychological Evaluation in the Differential Diagnosis Between Late-Onset Primary Progressive Aphasia Semantic Variant (PPA-SV) Versus Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE): A Case Report

Objective:Primary progressive aphasia semantic variant (PPA-SV) is an atypical dementia subtype on the frontotemporal dementia (FTD) spectrum. PPA-SV is clinically defined by naming and semantic deficits, with progressive language decline that generalizes to other domains over time. Typically, it presents as an early-onset dementia with TDP-43 pathology, but 33-46% of PPA-SV cases display initial onset after age 65 with potentially different clinical features. Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE), a more recently discovered neurodegenerative entity, is defined by an older age of onset, hippocampal sclerosis/atrophy, and TDP-43 pathology with a gradually progressive amnestic profile that expands to other cognitive deficits over time. The authors present a case report with overlapping features and suspected TDP-43 neuropathology ante-mortem for two reasons: first, to highlight the need for clinical criteria to formally diagnose LATE, and second, to address a gap in the literature on the possible clinical differences of late-onset PPA-SV.Participants and Methods:The authors present a case of a 78-year-old Indian bilingual man (English dominant) with 18 years of education, noncontributory medical history, and gradually progressive cognitive complaints reported over the past few years who was seen for outpatient neuropsychological evaluation. Prior workup was notable for negative amyloid PET scan, negative p-tau 217 blood test, and abnormal brain MRI revealing marked bilateral hippocampal atrophy with ex vacuo ventriculomegaly and minimal cerebrovascular disease. He scored 23/30 on prior MMSE, was diagnosed with amnestic MCI, prescribed Namenda and Exelon, and complained of minor memory and word-finding difficulties with reportedly intact IADLs and no signs of NPH.Results:Neuropsychological testing revealed a profound dysnomia (RBANS Naming raw score = 1/10), and he provided 0 words on two semantic fluency tasks but 15 words on letter fluency. Receptive vocabulary score was also impaired (PPVT-4, &lt;1st %). Memory performance also demonstrated rapid forgetting of information (RBANS List Recall raw = 0/10, Story Recall raw = 0/12) with no benefit to recognition cues (RBANS List Recognition raw = 12/20), but slightly better visual memory recall, albeit still impaired (RBANS Figure Recall raw = 4/20). Grooved pegboard scores were significantly worse with right-hand than left-hand. Irregular word reading (NAART = 16th %ile) was significantly below expectations and thought to reflect more of a surface dyslexia rather than a cultural confounder given that he has lived in the US for over 50 years and his occupational and educational history was completed in English.Conclusions:Results support the clinical utility of neuropsychological evaluation in the differential diagnosis to support a predominant clinical syndrome of PPA-SV despite overlapping features with LATE and suspected TDP-43 pathology. This case report highlights the diagnostic issue with the lack of literature describing the typical clinical progression or suggested diagnostic criteria of LATE. These findings also indicate that late-onset PPA-SV may include greater memory deficits earlier in the course, but this may also be a clinical masquerade that is more reflective of the extent of language deficits. Further research on late-onset manifestations of PPA-SV and LATE consensus clinical guidelines is advised.

Clinical authorization of amyloid PET in France: Towards a more precise diagnosis of Alzheimer's disease

The recent clinical authorization of amyloid PET in France represents a crucial step for the nuclear medicine community involved in the diagnosis of Alzheimer's disease (AD). At the era of ATN (Amyloid, Tau, Neurodegeneration) biomarkers, amyloid PET fills a need in patients with an atypical or mixed clinical presentation, in particular young patients (<65 years old), when the lumbar puncture is contraindicated or not feasible for technical reasons. Importantly, a negative amyloid PET scan discards the diagnosis of AD. Furthermore, early phase imaging of amyloid PET allows to estimate the perfusion neuronal state, increasing the diagnostic value of such PET radiotracer. Its role could be further developed in routine care for the selection and monitoring of promising disease modifiers therapies.

Plasma phosphorylated tau181 predicts cognitive and functional decline.

To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort. Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N=91) or AD dementia (N=64), and NC (N=241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N=70), MCI (N=75), and AD dementia (N=50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform. Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia. Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline.

Amyloid Negative, Highly Tau Positive: Clinical Characterization of a Rare Biomarker Profile

AbstractBackgroundThe majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).MethodWe searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) &gt; 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold &gt; 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).ResultAmong A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).ConclusionA‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.

A-252 A Suspected Case Of Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE) in an Older Adult

Abstract Objective: LATE is a common but underrecognized neuropathology that causes a progressive amnestic syndrome in older adults which mimics an Alzheimer’s disease (AD) clinical profile. Method: A 75-year-old female with a history of progressive cognitive impairment presented to a multidisciplinary neurology clinic. Neurocognitive screening during her neurological exam showed an amnestic memory profile. A work-up for medical causes for her cognitive impairment was negative. She had prominent hippocampal atrophy on MRI with a negative amyloid PET scan, raising concerns for LATE. She was referred for a comprehensive neuropsychological evaluation. Results: Neuropsychological testing confirmed an amnestic mild dementia profile in the context of her other cognitive skills (e.g., attention, executive functioning, processing speed, word finding, and visuospatial abilities) being largely preserved. On self-report questionnaires, the patient denied having any significant symptoms of depression or anxiety. Conclusions: LATE is described as causing a primarily amnestic neurocognitive profile with associated hippocampal atrophy and this was well demonstrated in our patient. While the diagnosis of LATE cannot be definitively made until autopsy, the absence of amyloid on her PET scan highly suggests a non-AD pathology like LATE. A limitation of the evaluation is that tau biomarker tests were not performed, making primary age-related tauopathy (PART) another possible pathology or co-pathology. Overall, this case study illustrates the importance of multidisciplinary assessment to help facilitate differential diagnosis for neurodegenerative conditions associated with amnestic cognitive impairment, especially when a non-AD pathology is suspected.

The impact of subthreshold levels of amyloid deposition on conversion to dementia in patients with amyloid-negative amnestic mild cognitive impairment

BackgroundAbout 40–50% of patients with amnestic mild cognitive impairment (MCI) are found to have no significant Alzheimer’s pathology based on amyloid PET positivity. Notably, conversion to dementia in this population is known to occur much less often than in amyloid-positive MCI. However, the relationship between MCI and brain amyloid deposition remains largely unknown. Therefore, we investigated the influence of subthreshold levels of amyloid deposition on conversion to dementia in amnestic MCI patients with negative amyloid PET scans.MethodsThis study was a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain magnetic resonance imaging, and [18F]-florbetaben (FBB) positron emission tomography scan (PET). Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Regional cortical amyloid levels were calculated, and a receiver operating characteristic (ROC) curve for conversion to dementia was obtained. To increase the reliability of the results of the study, we analyzed the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset together.ResultsDuring the follow-up period, 36% (39/107) of patients converted to dementia from amnestic MCI. The dementia converter group displayed increased standardized uptake value ratio (SUVR) values of FBB on PET in the bilateral temporal, parietal, posterior cingulate, occipital, and left precuneus cortices as well as increased global SUVR. Among volume of interests, the left parietal SUVR predicted conversion to dementia with the highest accuracy in the ROC analysis (area under the curve [AUC] = 0.762, P < 0.001). The combination of precuneus, parietal cortex, and FBB composite SUVRs also showed a higher accuracy in predicting conversion to dementia than other models (AUC = 0.763). Of the results of ADNI data, the SUVR of the left precuneus SUVR showed the highest AUC (AUC = 0.596, P = 0.006).ConclusionOur findings suggest that subthreshold amyloid levels may contribute to conversion to dementia in patients with amyloid-negative amnestic MCI.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Agreement of amyloid PET and CSF biomarkers in a clinical cohort

AbstractBackgroundThe amyloid deposition (A) in the 2018 ATN classification of Alzheimer disease can be assessed by CSF Aβ 1‐42 or amyloid PET. Although the agreement between them is high, it is not exact.MethodWe selected patients from the Alzheimer’s disease and other cognitive disorders Unit at Hospital Clínic of Barcelona with available amyloid PET and lumbar puncture, with a maximum difference of time of one and a half year between them. We used F18 Florbetapir (n=27), F18 Florbetaben (n=7), F18 Flutemetamol (n=16) or 11C‐PIB (n=2) as tracers for amyloid PET. CSF Aβ 1‐42, total tau (tTau) and phosphorylated tau (pTau) were measured using INNOTEST® Fujirebio until June 2019 and using LUMIPULSE® Fujirebio after June 2019. We analyzed the agreement between amyloid PET and CSF biomarkers.ResultWe included 52 patients. They had been diagnosed of Alzheimer disease (n=32), frontotemporal dementia (n=11), Lewy body disease (n=2) and psychiatric disorders (n=7) (Table 1).There was a perfect agreement between CSF biomarkers and amyloid PET when CSF biomarkers were all normal or all altered (Figure 1): All patients with CSF A+T+N+ (n=19) had a positive amyloid PET and all patients with CSF A‐T‐N‐ (n=7) had a negative amyloid PET. Agreement decreased with other CSF results. Only 11/19 patients with CSF A+T‐N‐ had a positive amyloid PET. 31/32 (97%) patients with positive amyloid PET had low Aβ 1‐42 levels (A+) but only 11/20 (55%) patients with negative amyloid PET had normal Aβ 1‐42 levels (A‐).ConclusionCSF biomarkers and amyloid PET showed a perfect agreement when CSF biomarkers were all normal or all altered. For other CSF ATN results, agreement with amyloid PET was much lower.

Application of histopathologically derived 3D tau burden map as in‐vivo region of interest for biomarker analysis

AbstractBackgroundQuantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease neuropathologic change, and showed relatively greater NFT burden in the anterior vs. posterior MTL. We investigated whether in‐vivo MRI and PET measures in ROIs derived from this map show meaningful biological relationships.MethodMultimodal in‐vivo imaging data from 292 participants in the Aging Brain Cohort were used. The group‐level NFT burden map was mapped to each participant’s MRI to define an ROI mask, further divided into anterior (aMTL) and posterior (pMTL) ROIs. Cortical thickness (N=292) and 18F‐Flortaucipir SUVR maps (N=86) were computed. Participants’ age was correlated with average thickness in the aMTL, pMTL, and anatomically defined MTL ROIs. 18F‐Flortaucipir uptake was compared between aMTL and pMTL. The analyses were repeated in subsets of cognitive normal participants, and those with negative amyloid PET scans.ResultCortical thickness in the aMTL ROI showed stronger correlation with age than pMTL and anatomically defined MTL subregional thickness. A polynomial fit provided the best age regression, with older participants showing a parabolic decline in thickness around age 60, when substantial NFT accumulation begins in MTL. Further, tau tracer uptake in aMTL was slightly but significantly higher than in pMTL (SUVR 1.19 vs. 1.18, p=0.02).ConclusionWe demonstrate the potential use of ex‐vivo NFT burden maps for in‐vivo image analysis. NFT deposition is particularly prominent in the anterior MTL in cases without or with low amyloid burden and at early Braak stage. Prior work suggests that even in the absence of amyloid, this tangle pathology may drive neurodegeneration in the aging population. Here we show that cortical thickness, a biormarker for neurodegeneration, when measured within a histopathologically‐defined region enriched for PART NFTs in the aMTL, is better correlated with age than when measured within anatomically defined subregions, suggesting that the relationship may be driven by PART. Greater tau tracer uptake in the aMTL ROI further supports this notion.

Improved comparability between measurements of mean cortical amyloid plaque burden derived from different PET tracers using multiple regions‐of‐interest and machine learning

AbstractBackgroundThe conversion of standard uptake value ratios (SUVRs) to Centiloid units using previously described methods has partially but not completely improved the ability to compare measurements of mean cortical amyloid plaque burden, classify positive versus negative amyloid PET scans, assess changes over time, and evaluate amyloid‐modifying treatment effects using different radiotracers. Here, we demonstrate improved harmonization between PiB and florbetapir (FBP) PET measurements of mean cortical SUVRs (mcSUVRs) using multiple regions‐of‐interest (ROIs) and machine learning algorithms.MethodsPiB and FBP PET image pairs from 91 subjects in the Open Access Series of Imaging Studies (https://www.oasis‐brains.org/) were used as the training set to optimize the algorithms to generate each subject’s pseudo‐PiB mcSUVR measurements from his or her FBP multi‐ROI SUVRs . PiB and FBP image pairs from 46 subjects in the Avid‐related Centiloid Project (www.gaain.org/centiloid‐project) were then used as the test set to compare Pearson’s correlation coefficients (r) between the pseudo and actual PiB mcSUVR measurements using our approach to that used in the Centiloid method. SUVRs with cerebellar reference were extracted from multi‐ROIs using FreeSurfer with partial volume correction. Pseudo mcSUVRs were generated using ensemble regression, partial least square regression (PLSR) and artificial neural network (ANN) separately, and their correlations with the actual PiB mcSUVR were compared to the PiB‐FBP correlation on Centiloid in both training and test sets.ResultsIn the training set, the Centiloid based PiB‐FBP correlation was r=0.904. An ANN with 7/6 neurons in the 1st/2nd hidden layers improved it to 0.987 (p≤8.3e‐12) and PLSR to 0.973 (p≤3.8e‐5). In the independent test set, ANN improved r to 0.981 from 0.927 (p≤6.6e‐4) and PLSR to 0.964 (p=0.011). Ensemble regression did not improve r.ConclusionThe ANN and PLSR algorithms mapping multi‐ROI FBP SUVRs to PiB mcSUVR appear to increase the comparability between measurements of mean cortical amyloid plaque burden using different PET tracers. Additional studies are needed to demonstrate the generalizability to other amyloid PET tracers, clarify its comparability in distinguishing between positive and negative amyloid PET scans, demonstrate its value in longitudinal studies and clinical trials, and extend our approaches to different tau PET ligands.

The role of amyloid PET in patient selection for extra-ventricular shunt insertion for the treatment of idiopathic normal pressure hydrocephalus: A pooled analysis

BackgroundIdiopathic Normal Pressure Hydrocephalus (iNPH) can be effectively treated through shunt insertion. However, most shunted patients experience little or no clinical benefit, which suggests suboptimal patient selection. While contentious, multiple studies have reported poorer shunt outcomes associated with concomitant Alzheimer’s disease. Prompted by this observation, multiple studies have assessed the role of amyloid PET, a specific test for Alzheimer’s disease, in patient selection for shunting. MethodsA comprehensive literature search was performed to identify studies that assessed the association between amyloid PET result and the clinical response to shunting in patients with suspected iNPH. Pooled diagnostic statistics were calculated. ResultsAcross three relevant studies, a total of 38 patients with suspected iNPH underwent amyloid PET imaging and shunt insertion. Twenty-three patients had a positive clinical response to shunting. 18/28 (64.3%) of patients with a negative amyloid PET and 5/10 (50%) with a positive amyloid PET had a positive response to shunting. The pooled sensitivity, specificity and accuracy was 33.3%, 76.2% and 58.3%. None of these statistics reached statistical significance. ConclusionThe results of this pooled analysis do not support the selection of patients with suspected iNPH for shunting on the basis of amyloid PET alone. However, due to small cohort sizes and weakness in study design, further high-quality studies are required to properly determine the role of amyloid PET in assessing this complex patient group.

Prognostic Impact of 18-F-Florbetaben Amyloid PET Imaging in Patients with Isolated Increases in Cerebrospinal Fluid Phospho-Tau Biomarkers: A Longitudinal Study.

This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer's disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75%(6/8) for positive and 35%(6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.

Diagnostic value of amyloid-PET and tau-PET: a head-to-head comparison

PurposeAssess the individual and combined diagnostic value of amyloid-PET and tau-PET in a memory clinic population.MethodsClinical reports of 136 patients were randomly assigned to two diagnostic pathways: AMY-TAU, amyloid-PET is presented before tau-PET; and TAU-AMY, tau-PET is presented before amyloid-PET. Two neurologists independently assessed all reports with a balanced randomized design, and expressed etiological diagnosis and diagnostic confidence (50–100%) three times: (i) at baseline based on the routine diagnostic workup, (ii) after the first exam (amyloid-PET for the AMY-TAU pathway, and tau-PET for the TAU-AMY pathway), and (iii) after the remaining exam. The main outcomes were changes in diagnosis (from AD to non-AD or vice versa) and in diagnostic confidence.ResultsAmyloid-PET and tau-PET, when presented as the first exam, resulted in a change of etiological diagnosis in 28% (p = 0.006) and 28% (p < 0.001) of cases, and diagnostic confidence increased by 18% (p < 0.001) and 19% (p < 0.001) respectively, with no differences between exams (p > 0.05). We observed a stronger impact of a negative amyloid-PET versus a negative tau-PET (p = 0.014). When added as the second exam, amyloid-PET and tau-PET resulted in a further change in etiological diagnosis in 6% (p = 0.077) and 9% (p = 0.149) of cases, and diagnostic confidence increased by 4% (p < 0.001) and 5% (p < 0.001) respectively, with no differences between exams (p > 0.05).ConclusionAmyloid-PET and tau-PET significantly impacted diagnosis and diagnostic confidence in a similar way, although a negative amyloid-PET has a stronger impact on diagnosis than a negative tau-PET. Adding either of the two as second exam further improved diagnostic confidence.Trial numberPB 2016-01346.

Phenotypes associated with MAPT duplications

AbstractBackgroundDuplication of the 17q21.3 region, leading to increased MAPT expression, causes a rare atypical early‐onset dementia (EOD) mimicking Alzheimer’s Disease (AD) clinical presentation. Since our initial report in 2016, the same duplication has been identified in additional patients including 2 progressive supranuclear palsy (PSP) patients. It remains unclear whether MAPT duplication‐associated phenotypes are purely cognitive and if clinical and neuroimaging data are suggestive of a pure tauopathy or an amyloid plus tau underlying pathology.MethodWe report in this study clinical and paraclinical data from 10 MAPT duplication carriers, including 8 with a clinical EOD presentation and two recently identified during the screening of a series of PSP cases. All clinical data were collected as well as family history, neuropsychological assessment, 3D‐structural MRI (n = 7 patients), fluorodesoxyglucose‐PET (n = 5), DaTSCAN SPECT (n = 2), Amyloid‐PET (n = 3) and Tau‐PET (n = 2). Six patients had AD cerebrospinal fluid (CSF) biomarkers measured. Results were interpreted following Amyloid/Tau/Neurodegeneration (A/T/N) classification.ResultAmong the 10 patients, 6 had a positive family history of EOD, with cosegregation in one family. In one of the 4 sporadic patients, we could demonstrate that the duplication occurred de novo. Mean age of onset was 50.4 years [37‐58]. Eight presented a pure cognitive decline with an initial episodic amnesic syndrome. A behavioral dysexecutive syndrome was found in 5 patients (50%). Two patients were diagnosed as PSP but no or minor extrapyramidal signs were found among the 8 cognitive patients, despite 2 DaTSCANS showing presynaptic dopaminergic denervation. MRI of 6 cases (86%) showed hippocampal and temporoparietal bilateral atrophy. All CSF biomarkers were T+ and N+. Amyloid CSF biomarkers were abnormal in 3/6, suggestive of A+, however all three had negative amyloid‐PET. Interestingly, both Tau‐PET imaging showed strong deposits of Tau pathology within mesiotemporal regions and mild frontal cortex uptake in one patient (Figure). The neuropathology of two patients is currently being examined and will be presented.ConclusionThis largest series of MAPT duplications carriers shows a heterogeneous expression with clinical and neuroimaging data suggesting mixed cortical and subcortical impairment with diverse clinical consequences. We will confront these data to the results of the neuropathological examinations.

Challenges in Alzheimer's Disease Diagnostic Work-Up: Amyloid Biomarker Incongruences.

Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. 1) To verify that cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen's K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET-). FDG-PET and all CSF markers (Aβ42, AβR, p-Tau, t-Tau) were suggestive of Alzheimer's disease (AD) in 5 of these 6 cases. 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET-discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.