PiB-PET Imaging Research Articles

Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

Alzheimer disease (AD) copathologies of β-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid β-amyloid (A) and tau (T) were acquired. The association of functional cognition, β-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aβ does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

Mitochondrial alterations in fibroblasts from sporadic Alzheimer's disease (AD) patients correlate with AD-related clinical hallmarks

Mitochondrial dysfunctions are key features of Alzheimer’s disease (AD). The occurrence of these disturbances in the peripheral cells of AD patients and their potential correlation with disease progression are underinvestigated. We studied mitochondrial structure, function and mitophagy in fibroblasts from healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, namely, (i) Mini-Mental State Examination (MMSE) and (ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB), and with (iii) amyloid beta (Aβ) plaque burden (PiB-PET imaging) and (iv) the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). We revealed alterations in mitochondrial structure as well as specific mitochondrial dysfunction signatures in AD-MCI and AD-D fibroblasts and revealed that defective mitophagy and autophagy are linked to impaired lysosomal activity in AD-D fibroblasts. We reported significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. This study emphasizes the potential use of peripheral cells for investigating AD pathophysiology.

Sensitivity of NIH ToolBox Motor tests to detect amyloid positivity in cognitively normal older adults

AbstractBackgroundChanges in motor functioning and particularly lower motor functioning such as balance and gait have been shown to be an early predictor of dementia (Kueper et al 2017). Based on these results, it has been suggested that balance and gait measures should be a regular component of a clinical dementia risk evaluation. The NIH Toolbox (NIHTB) has developed motor‐based tasks along with its cognitive battery. The aim of this study was to evaluate the utility of several of the NIHTB‐Motor task performance to predict amyloid status in cognitively normal older adults.MethodData from 45 cognitively normal adults age 65+ who were part of a larger study examining changes in driving behavior as predictors of cognitive decline were included in this study. Participants were divided into two groups based on PiB PET imaging and amyloid positivity determined using a centiloid scale: values ≥20 were considered positive, values ≤10 were negative; values between 10 and 20 were considered indeterminate and not included (n = 9)). Twenty nine participants were amyloid negative (OCN‐) and 16 were positive (OCN+). Data from the standing balance, grip strength and 2‐minute walking endurance tasks were analyzed using independent sample t‐tests.ResultThere were no differences in age or education between the two groups. However, there was a significant correlation between age and standing balance uncorrected score. As a result, fully corrected scores were used for this analysis. There was a significant difference between the OCN‐ and OCN+ for the fully corrected standing balance standard score (t = 1.7, p&lt;0.04) such that the OCN+ group had lower balance scores compared to the OCN‐ group. No significance differences were found for grip strength or the 2‐minute walking endurance task.ConclusionThe Standing Balance task from the NIHTB may be a sensitive marker to identify individuals who are at higher risk of developing cognitive impairment and dementia. The NIHTB tasks were designed to be easy to administer in a relatively short amount of time with normative data, and these results suggest the Standard Balance task should be included as a routine measure of dementia risk.

Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech.

The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer's disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.

Estimation of brain amyloid accumulation using deep learning in clinical [11C]PiB PET imaging

IntroductionEstimation of brain amyloid accumulation is valuable for evaluation of patients with cognitive impairment in both research and clinical routine. The development of high throughput and accurate strategies for the determination of amyloid status could be an important tool in patient selection for clinical trials and amyloid directed treatment. Here, we propose the use of deep learning to quantify amyloid accumulation using standardized uptake value ratio (SUVR) and classify amyloid status based on their PET images.MethodsA total of 1309 patients with cognitive impairment scanned with [11C]PIB PET/CT or PET/MRI were included. Two convolutional neural networks (CNNs) for reading-based amyloid status and SUVR prediction were trained using 75% of the PET/CT data. The remaining PET/CT (n = 300) and all PET/MRI (n = 100) data was used for evaluation.ResultsThe prevalence of amyloid positive patients was 61%. The amyloid status classification model reproduced the expert reader’s classification with 99% accuracy. There was a high correlation between reference and predicted SUVR (R2 = 0.96). Both reference and predicted SUVR had an accuracy of 97% compared to expert classification when applying a predetermined SUVR threshold of 1.35 for binary classification of amyloid status.ConclusionThe proposed CNN models reproduced both the expert classification and quantitative measure of amyloid accumulation in a large local dataset. This method has the potential to replace or simplify existing clinical routines and can facilitate fast and accurate classification well-suited for a high throughput pipeline.

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease.

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

AbstractBackgroundThe current shift towards (early) secondary intervention AD trial designs warrants the need for detection of subtle changes of both amyloid‐β (Aβ) burden and cognitive functioning. This study investigated the longitudinal trajectory of global and regional Aβ measurements and their value in predicting cognition in initially cognitively unimpaired (CU) subjects.MethodWe included 133 CU subjects with available longitudinal cognition (MMSE: 2‐13 assessments, 7.9±2.5 years; neuropsychological memory tasks: 2‐5 assessments, 4.0±1.9 years) and [11C]PiB PET imaging (2‐5 scans, 4.4±1.9 years) from the OASIS‐3 cohort. Baseline and annualized Aβ measures (DVR) were computed for a global composite and 4 clusters of regions, reflecting different stages of the amyloid accumulation process. Linear mixed effect models were used to examine the predictive value of Aβ measurements (i.e. Aβbaseline, Aβslope, and Aβbaseline*slope) on global cognition (MMSE) and several aspects of memory performance. All analyses were controlled for age, sex, years of education, and time between baseline PET and first cognitive assessment.ResultGlobal baseline amyloid burden and slope were non‐linearly related (). This was also apparent in stages 1, 2, and 3 clusters, but less in stage 4 (). MMSE performance over time could only be predicted by Aβ burden and accumulation in cluster 2 (precuneus, lateral orbitofrontal (LOFC), and insula; β baseline=‐0.37, p&lt;.001; β interaction=14.16, p&lt;.05). Focusing on the precuneus ROI by itself significantly improved the model (βbaseline =‐0.29, p&lt;.001; βslope =‐9.71, p&lt;.05; βinteraction =8.71, p&lt;.01), where fast‐decliners were those at the plateau phase of accumulation (). Similarly, precuneal slope and the interaction term were both predictive of changes in immediate (βslope =‐60.95, p&lt;.05; βinteraction =53.39, p&lt;.05) and delayed episodic memory (βslope =‐65.45, p&lt;.05; βinteraction =53.14, p&lt;.05). In the Aβ‐ at baseline group (N=93), LOFC slope and the interaction term predicted changes in working (βslope =‐172.0, p&lt;.05; βinteraction =‐147.2, p&lt;.05) and semantic memory performance (βslope =‐439,4, p&lt;.01; βinteraction =393.1, p&lt;.01).ConclusionQuantifying longitudinal and regional changes in Aβ can improve the prediction of future cognitive functioning in initially CU individuals. For individuals with established amyloid pathology, longitudinal Aβ measures help to identify those subjects most likely to show cognitive decline within the short timelines of clinical trials.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.

Longitudinal assessment of amyloid-beta deposition in initially amyloid-negative non-demented individuals with [11C]-PIB PET imaging.

This study aimed to assess the longitudinal changes in amyloid beta (Aβ) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60–75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ± 1.4 years (converter). The global PIB DVR in converters increased from 1.22 ± 0.07 at baseline to 1.63 ± 0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ± 0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ± 0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ± 0.5 years of follow-up, which was faster than 5.0 ± 2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aβ deposition in the lateral temporal cortex and/or frontal cortex.

Longitudinal assessment of amyloid‐beta deposition in initially amyloid‐negative individuals with [11C]‐PIB PET imaging

AbstractBackgroundThe earlier stage of amyloid‐beta (Aβ) deposition, before Aβ is widespread throughout cortex, remains poorly understood. The longitudinal change of Aβ deposition was evaluated with [11C]‐PIB PET in initially amyloid‐negative subjects.MethodSixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (age 60‐75 years) who were amyloid‐negative at baseline underwent cognitive assessment and 60‐min dynamic [11C]‐PIB PET at two or more over 5.0 to 9.4 years of a long follow‐up, and apolipoprotein‐E (APOE) genotype assessment. Regions of interest were defined in the bilateral cortex on co‐registered MRI. A quantitative analysis for [11C]‐PIB was used with the distribution value ratio (DVR). Longitudinal changes in PIB DVR values were evaluated in the same regions and an annual rate of change in PIB DVR was calculated.ResultSeven (30.4%) of 23 initially amyloid‐negative subjects converted to be globally amyloid‐positive (global DVR ≥1.40) over a follow‐up of 6.5±1.4 years (converter). A global DVR increased from 1.22±0.07 at baseline to 1.63±0.15 (n=7, p&lt;0.01) at a last follow‐up. In contrast, in the 16 subjects, a global DVR was 1.15±0.07 at baseline and did not change over a follow‐up period (stable). An annual increase of global DVR in converters was 0.057±0.019 per year (n=7, p&lt;0.01), larger than that in stable subjects (0.004 ± 0.013, n=16). An increase of global DVR was not correlated with baseline global DVR (r=0.26, n=23, p=0.22) or baseline age (r=0.15, n=23, p=0.47). Four (66.6%) of 6 APOE ε4 carriers converted to be amyloid‐positive while 3 (17.6%) of 17 APOE ε4 non‐carriers did (Fisher’s exact p&lt;0.05). Among cortical regions, regional DVR in the lateral temporal cortex increased to 1.48±0.06 (n=6) above regional positivity threshold over 2.9±1.5 years of a follow‐up and its period was the shortest. Furthermore, an increase of regional DVR prior to reaching the globally positive threshold was 0.084±0.050 per year in the precuneus, which was the largest.ConclusionAmyloid‐negative individuals, especially with APOE ε4, could convert to be globally amyloid‐positive with extensive cortical spread of Aβ, based on an early Aβ deposition in lateral temporal cortex and a large increase of Aβ deposition in precuneus.

Associations between lifestyle risk, β‐amyloid, tau, and cognition in late mid‐life

AbstractBackgroundModifiable lifestyle risk (LR) factors are increasingly viewed as preventive strategies for AD and dementia; however, the impact of LR factors on AD biomarkers or AD biomarker‐related cognitive decline remains unknown. We utilized the Lifestyle for BRAin health (LIBRA) index 1)to investigate whether baseline LR predicts incident cognitive impairment and/or β‐amyloid onset; 2)to examine the effect of longitudinal LR on cognitive decline in the presence of β‐amyloid; 3)to preliminarily examine the cross‐sectional relationship between late‐midlife LR and β‐amyloid and tau biomarker groups.MethodParticipants (n=1244, Table 1) from the Wisconsin Registry for Alzheimer’s Prevention completed serial health and neuropsychological assessments with a subset undergoing PiB PET imaging (n=238) and MK‐6240 (n=186) PET imaging. Cox regressions assessed the predictive utility of baseline LIBRA for incident cognitive impairment (1.5 SD below covariate adjusted 3‐test Preclinical Alzheimer’s Cognitive Composite, PACC‐3) and β‐amyloid duration (i.e. age at assessment – estimated age PiB(+)). Linear mixed models examined the main effects and age interactions of LIBRA and β‐amyloid duration on longitudinal cognitive performance. Group differences in LIBRA were assessed across biomarker groups, where amyloid (A+) and tau (T+) positivity were defined as a global PiB DVR&gt;1.19 and entorhinal cortex MK‐6240 SUVR&gt;1.27, respectively.ResultIn the survival analysis, baseline LIBRA predicted risk for incident cognitive impairment of subjects unimpaired at baseline (HR=1.18; Figure 1). In the amyloid imaging subset, baseline LIBRA did not predict β‐amyloid onset (HR=0.85; Figure 1). Linear mixed effects models indicated a significant main effect of LIBRA (higher LIBRA risk = worse PACC‐3) and a significant interaction of β‐amyloid duration×age on PACC‐3 (longer β‐amyloid duration = faster PACC‐3 decline; Figure 2). In the combined imaging subset (n=186), there were no differences in LIBRA across biomarker groups (Kruskal‐Wallis H: 5.08, p=.166; Figure 3).ConclusionThese findings suggest that a healthy lifestyle is associated with overall cognitive performance but not the rate of cognitive decline or biomarker status. In this sample, LR did not influence the onset of β‐amyloid or hasten AD‐related cognitive decline. Replication of this finding and future work is necessary to better understand the relationships between LR factors, cognitive decline and AD.

Neuropsychological, clinico‐pathologic, neuroimaging, and biomarker profiles of the MGH FTD Unit posterior cortical atrophy (PCA) cohort

AbstractBackgroundObjective: To present comprehensive data on the MGH FTD Unit PCA cohort. PCA is a neurodegenerative clinical syndrome usually arising from Alzheimer’s Disease (AD) neuropathologic changes (ADNC). While visuoperceptual and spatial problems are typical early presenting symptoms, patients also report problems with spelling, calculation, and word retrieval. Due to significant heterogeneity in the syndrome, further classification of PCA by subtypes based on predominant cognitive impairments (dorsal, ventral, caudal, dominant parietal) has also been proposed. We launched our multidisciplinary MGH PCA program in 2008 to address the special care needs of this population, and to advance our scientific understanding of PCA and its treatment.Methods39 participants were recruited for research participation based on clinical diagnostic criteria consistent with PCA, including a dominant hemisphere variant (i.e., progressive Gerstmann‐like syndrome minimal visuospatial disturbance). Participants underwent structured review of symptoms and history; systematic neurological exam; comprehensive neuropsychological and speech‐language assessments; multimodal imaging (MRI and/or functional MRI and FDG, amyloid, and tau PET); and CSF analysis. Some patients have come to autopsy. We used the Neuropsychological Assessment Rating (NAR) scale to quantify performance in cognitive domains pertinent to PCA and for subtype classification.ResultsOf seven individuals for whom we have autopsy‐confirmed neuropathology, five had ADNC; one had lobar atrophy and tau pathology in a cortico‐basal degeneration (CBD) distribution; and one had Frontotemporal Lobar Degeneration TDP43 Type A (GRN mutation). 22 patients had biomarkers consistent with ADNC (17 with elevated PiB PET imaging signal, 5 with AD‐like CSF ). Mean NAR domain scores (impairment level ratings: 0=Normal, .5=questionable/very mild, 1=mild, 2= moderate, 3=severe) revealed relatively normal Attention/Processing Speed (0.2); mildly impaired Executive Function (0.8) and Memory (1.1); questionably/very mildly impaired Language (0.5); and moderately impaired Visuospatial Function (2).ConclusionThe MGH PCA program has a robust cohort of patients with a comprehensive data set that includes standardized characterization of the PCA neurocognitive and neurologic profiles, high‐resolution MRI (structural, functional), multimodal PET imaging, CSF biomarkers, and in some cases neuropathology. This data set will allow for detailed examination and improved understanding of this atypical neurodegenerative syndrome. Additional analyses are ongoing, including tau imaging profiles.

Detecting Amyloid Positivity in Elderly With Increased Risk of Cognitive Decline.

The importance of early interventions in Alzheimer’s disease (AD) emphasizes the need to accurately and efficiently identify at-risk individuals. Although many dementia prediction models have been developed, there are fewer studies focusing on detection of brain pathology. We developed a model for identification of amyloid-PET positivity using data on demographics, vascular factors, cognition, APOE genotype, and structural MRI, including regional brain volumes, cortical thickness and a visual medial temporal lobe atrophy (MTA) rating. We also analyzed the relative importance of different factors when added to the overall model. The model used baseline data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) exploratory PET sub-study. Participants were at risk for dementia, but without dementia or cognitive impairment. Their mean age was 71 years. Participants underwent a brain 3T MRI and PiB-PET imaging. PiB images were visually determined as positive or negative. Cognition was measured using a modified version of the Neuropsychological Test Battery. Body mass index (BMI) and hypertension were used as cardiovascular risk factors in the model. Demographic factors included age, gender and years of education. The model was built using the Disease State Index (DSI) machine learning algorithm. Of the 48 participants, 20 (42%) were rated as Aβ positive. Compared with the Aβ negative group, the Aβ positive group had a higher proportion of APOE ε4 carriers (53 vs. 14%), lower executive functioning, lower brain volumes, and higher visual MTA rating. AUC [95% CI] for the complete model was 0.78 [0.65–0.91]. MRI was the most effective factor, especially brain volumes and visual MTA rating but not cortical thickness. APOE was nearly as effective as MRI in improving detection of amyloid positivity. The model with the best performance (AUC 0.82 [0.71–0.93]) was achieved by combining APOE and MRI. Our findings suggest that combining demographic data, vascular risk factors, cognitive performance, APOE genotype, and brain MRI measures can help identify Aβ positivity. Detecting amyloid positivity could reduce invasive and costly assessments during the screening process in clinical trials.

Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer\u2019s disease and PET amyloid-positive patient identification

BackgroundCerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer’s disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer’s disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge.MethodsIn the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer’s disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods.ResultsIn the first cohort, pT217 but not pT181 differentiated between Alzheimer’s disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer’s disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P < 0.001).ConclusionsIncreased cerebrospinal fluid pT217 levels, more than those of pT181, are highly specific biomarkers for detecting both the preclinical and advanced forms of Alzheimer’s disease. This finding should greatly improve the diagnosis of Alzheimer’s disease, along with the correlations found to exist between pT217 levels and PiB-PET data. It also suggests that pT217 is a promising potential target for therapeutic applications and that a link exists between amyloid and tau pathology.

Longitudinal degradation of the default/salience network axis in symptomatic individuals with elevated amyloid burden.

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.

RETROSPECTIVE COGNITIVE DECLINE IS ASSOCIATED WITH NEUROFIBRILLARY TANGLES AND BETA-AMYLOID PLAQUES MEASURED BY [F-18]MK-6240 AND [C-11]PIB IN LATE-MIDDLE AGED PERSONS CLINICALLY UNIMPAIRED AT BASELINE

Characterizing contributions of neurofibrillary tangles (NFTs) and beta-amyloid (AB) plaques to cognitive decline, and relationships with other biomarkers during the preclinical phase of Alzheimer's disease (AD) may improve diagnostic and clinical trial outcomes. This work investigated if NFTs and AB plaques measured by PET explained differences in retrospective longitudinal cognitive trajectories of persons recruited from the Wisconsin Registry for Alzheimer's Prevention (WRAP) who were clinically unimpaired at their baseline cognitive assessment. Individuals (N=159; 59±6 years at baseline composite) recruited from WRAP underwent longitudinal cognitive assessments and T1-weighted MR, MK-6240 and PiB PET imaging. A preclinical Alzheimer's cognitive composite (PACC-3: RAVLT Total, WMS-R Logical Memory Delayed Recall, and WAIS-R Digit Symbol) was calculated (mean of Z-scored tests) for each assessment. Four biomarker groups (A+/-, T+/-) were established based on PiB (Global DVR >1.19; Reference Logan, cerebellum GM) and MK-6240 (Entorhinal cortex SUVR>1.27, mean+2SD of PIB(-) group; cerebellum GM, 70–90 min) PET. Differences in PACC-3 trajectories by group were interrogated using a linear mixed effects model with random person-level slopes and intercepts (model in Figure 1). Group differences in demographics, select neuropsychological tests, and biomarkers (PET, hippocampal volume, systolic blood pressure) were also investigated. The linear model indicated a significant group×time interaction (Figure 1); post-hoc pairwise comparisons (Tukey-adjusted) indicated the A+/T+ group had steeper PACC-3 decline compared to all other groups, but other groups did not differ significantly. Groups did not differ by sex, race, or family history of dementia, but did differ in the frequency of APOE-e4 carriers (Table 1). Systolic blood pressure and hippocampal volume did not differ by group at baseline or last assessments. RAVLT Total, WMS-R Logical Memory Delayed Recall, self-reported severity of memory problems, PACC-3 and the frequency of MCI differed by group at last assessment, but MMSE, self- and informant-reported memory problems, and WAIS-R Digit Symbol did not (Table 2).

Brain Amyloid-β Deposition and Blood Biomarkers in Patients with Clinically Diagnosed Alzheimer's Disease.

Brain amyloid-β (Aβ) deposition is a hallmark to define Alzheimer's disease (AD). We investigated the positive rate of brain amyloid deposition assessed with 11C-Pittsburgh compound (PiB)-PET and blood Aβ levels in a cohort of probable AD patients who were diagnosed according to the 1984 NINCDS-ADRDA criteria. Eighty-four subjects with a clinical diagnosis of probable AD dementia, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) status were subjected to PiB-PET and 18F-fluorodeoxyglucose (FDG)-PET scans. Plasma biomarkers of Aβ42, Aβ40, and T-tau were measured using single molecule array technology. The positive rate of PiB-PET, the associations between PiB-PET status and FDG-PET, plasma biomarkers, and clinical manifestations were analyzed. PiB-PET was positive in 77.36% of probable AD patients, 31.80% of MCI patients, and 0 of NC. Plasma Aβ42/Aβ40 ratio was associated with PiB-PET, the ROC curve analysis revealing an AUC of 0.77 (95% CI: 0.66-0.87), with a sensitivity of 82% and specificity of 64%. Some clinical manifestations were associated with PiB-PET imaging. Our findings indicate that only three-fourths of patients diagnosed with probable AD fit the pathological criteria, suggesting that we should be cautious regarding the accuracy of AD diagnosis when no biomarker evidence is available in our clinical practice.

S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies.

Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

Comparative study on neuropsychological tests for typical Alzheimer's disease, frontal variant of Alzheimer's disease and behavioral variant of frontotemporal dementia

Objective To compare the neuropsychological features and other clinical and imaging characteristics among patients with typical Alzheimer's disease (TAD), frontal variant Alzheimer's disease (fvAD) and behavioral variant frontotemporal dementia (bvFTD). Methods Neuropsychological scales were used to evaluate the cognitive function and neuropsychiatric symptoms of nine patients with fvAD, 30 patients with bvFTD and 32 patients with typical AD (TAD). The apolipoprotein E (ApoE) e4 allele and brain imaging techniques, including the magnetic resonance imaging (MRI), 11C-Pittsburgh compound B positron emission tomography (PIB-PET), and 18F-deoxyglucose positron emission tomography (FDG-PET), were used for the differential diagnosis of fvAD and bvFTD. Results There were no significant differences in general cognitive function or daily activity in patients among the three groups.However, the cognitive subscale scores of Montreal Cognitive Assessment (MoCA) scale, including visual acuity and executive function, delayed recall, and orientation, were significantly different among the groups (Z=7.891, P=0.035; Z=7.412, P=0.031; Z=6.437, P=0.043, respectively). The clock drawing test (CDT) score of TAD group was higher than that in the bvFTD and fvAD groups (Z=8.673, P=0.020), while the neuropsychological questionnaire (NPI) scores of the bvFTD and fvAD groups were higher than those of the TAD group (Z=7.577, P=0.023). Meanwhile, the incidences of agitation, disinhibition and abnormal behavior of NPI in the bvFTD and fvAD groups were higher than those in the TAD group (χ2=11.139, P=0.004; χ2=6.481, P=0.039; χ2=6.812, P=0.033, respectively). The frequencies of the ApoE e4 allele were 44.4% in the fvAD group and 33.3% in the bvFTD group, which were not significant different from that in the TAD group (40.6%). Furthermore, patients in the fvAD group were associated with decreased regional cerebral glucose metabolism and amyloid deposition in the temporal-parietal cortex evaluated by FDG-PET and PIB-PET. Conclusions Neuropsychological evaluation is valuable for the differential diagnosis of TAD, fvAD and bvFTD.The frequencies of the ApoEe4 allele are similar among the three groups.FDG-PET and PIB-PET imaging plays an important role in the diagnosis of variant types of Alzheimer's disease. Key words: Alzheimer disease; Frontal lobe; Dementia; Neuropsychological tests; Apolipoprotein E4; Positron-emission tomography

An association study between vascular risk factors and cognitive impairment using quantitative PiB-PET imaging

An association study between vascular risk factors and cognitive impairment using quantitative PiB-PET imaging