PiB PET Research Articles

11C]PiB and [18F]AV45 PET radiotracers show different rates of amyloid‐β clearance

AbstractBackgroundResults from the first Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) clinical trial showed Gantenerumab reduces amyloid‐β deposition in autosomal dominant Alzheimer disease individuals. However, it is uncertain whether these initial findings from [11C]PiB PET generalize to other amyloid‐β PET radiotracers.MethodWe acquired [11C]PiB and [18F]AV45 PET in mutation positive DIAN‐TU participants in the gantenerumab (n=30) and placebo drug arms (n=19). Participants were assessed at baseline and Year 4; at each visit, [11C]PiB and [18F]AV45 PET were acquired, with at most 28 days between imaging sessions. Regional standardized uptake value ratios (SUVRs) were quantified using the PET Unified Pipeline. Annualized SUVR percent change between baseline and Year 4 for both radiotracers in both drug arms were calculated. Differences in SUVR change between radiotracers/drug arms were assessed using the Wilcoxon signed‐rank/rank‐sum test. Each test statistic is reported as a rank‐biserial correlation r accompanied by p‐values adjusted for false discovery control by the Benjamini‐Hochberg procedure at level q=0.20.ResultWe observed a decrease from baseline to Year 4 SUVR in the gantenerumab arm, which was larger when studied with [11C]PiB than with [18F]AV45 PET in several regions, including the striatum and cingulate gyrus (r=[‐0.79,‐0.31], FDR‐adjusted p‐values=[0.00086,0.19], Figure 1). In contrast, we observed an increase in SUVR in the placebo arm, comparable in magnitude between [11C]PiB and [18F]AV45 PET (r=[‐0.15,0.68], FDR‐adjusted p‐values=[0.29,0.86]).ConclusionDifferences seen between the effects of gantenerumab in [11C]PiB versus [18F]AV45 PET suggest several regions, such as the striatum and cingulate gyrus, may be inappropriate for radiotracer harmonization in studies involving gantenerumab. More practically, the finding that anti‐amyloid‐β therapies may have different effects on signal across radiotracers suggests multi‐site studies of anti‐amyloid‐β treatments should agree on a single radiotracer for best results. Follow‐up postmortem studies will be conducted to determine the binding affinity of various amyloid‐β radiotracers to amyloid‐β plaques in this cohort.

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<.001; β interaction=14.16, p<.05). Focusing on the precuneus ROI by itself significantly improved the model (βbaseline =‐0.29, p<.001; βslope =‐9.71, p<.05; βinteraction =8.71, p<.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<.05; βinteraction =53.39, p<.05) and delayed episodic memory (βslope =‐65.45, p<.05; βinteraction =53.14, p<.05). In the Aβ‐ at baseline group (N=93), LOFC slope and the interaction term predicted changes in working (βslope =‐172.0, p<.05; βinteraction =‐147.2, p<.05) and semantic memory performance (βslope =‐439,4, p<.01; βinteraction =393.1, p<.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.

Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of patients with mixed pathology

AbstractBackgroundRecent studies on subjects with “pure” Alzheimer’s disease (AD) reported significant association between high blood neurofilament light chain (NfL) and AD‐related atrophy and poor cognition, but not with white matter hyperintensities (WMHs). In contrast, studies on non‐demented elderly with cerebral small vessel disease (CSVD) revealed a significant association between blood NfL and magnetic resonance imaging (MRI) markers of SVD including WMHs, lacunes and microbleeds. A major limitation of these studies is the lack of participants with mixed pathology to explore the potential independent and/or combined effects of brain atrophy, CSVD and amyloid burden (Aβ) on blood NfL.MethodThis study included 208 Singaporean participants of an ongoing longitudinal study, including non‐cognitively impaired controls (NCI; n=43), cognitively impaired no dementia (CIND; n=99), AD (n=44) and Vascular dementia (VaD; n=22). The presence of brain atrophy was defined by medial temporal atrophy scores ≥2. CSVD were determined by MRI markers. Brain Aβ was assessed by [11C]‐PiB PET SUVR. Plasma NfL (pNfL) was measured by Single molecule array (Simoa) immunoassay.ResultpNfL concentrations were significantly increased in AD and VaD. In the full cohort, stepwise regression including neuroimaging markers (brain atrophy, WMH, cerebral microbleeds, lacunes and brain Aβ), vascular risk factors (hypertension, hyperlipidemia, diabetes, smoking and APOE ε4 carriership) and demographics (age, gender, education) as independent variables showed that brain atrophy, WMH, age, gender and presence of diabetes to be independently associated with pNfL (all p<0.05). Further univariate general linear models (Fig 1) showed that in the presence of brain atrophy (N+WMH‐) or high WMH (N‐WMH+) alone, pNfL was significantly increased after controlling for age, gender and presence of diabetes (p≤0.007). There was a trend of further increase in pNfL in the presence of both brain atrophy and high WMH burden.ConclusionThe independent associations and potential combined effects of brain atrophy and WMH on pNfL, together with the high prevalence of SVD burden in the elderly, suggests that SVD needs to be considered when interpreting elevated pNfL in elderly patients.

White matter tract integrity, but not amyloid burden, is related to cognition in cognitively normal older adults

AbstractBackgroundThe increased focus on preclinical Alzheimer’s disease (AD) necessitates an understanding of how general biomarkers of neuronal injury and AD‐specific biomarkers differentially contribute to the cognitive performance in cognitively normal individuals. It has been suggested that alterations in limbic white matter (WM) tracts may precede both gray matter atrophy and clinical impairment (Teipel et al., 2016). However, few studies have evaluated whether limbic tract alterations are associated with cognitive performance in individuals with normal cognition. To address this gap, this cross‐sectional, multi‐modal imaging study examined whether measures of WM tract integrity, using diffusion tensor imaging (DTI) (including fornix, hippocampal cingulum, and uncinate fasciculus), were related to cognitive performance, independent of cortical amyloid burden in cognitively normal individuals.MethodAnalyses included 130 cognitively normal participants from the BIOCARD Study (Table 1) who completed cognitive assessments, diffusion‐weighted MR and 11C‐PiB PET imaging during their annual visit. Cognitive performance was captured by cognitive composite scores reflecting verbal episodic memory, executive function, and visuospatial processing. WM tract integrity was measured by fractional anisotropy (FA) and radial diffusivity (RD) in the 3 above‐mentioned ROIs. PiB PET amyloid positivity was derived from cortical distribution volume ratios (cDVR) using cerebellar gray matter as the reference.Linear regressions (covarying age, sex, and education) were used to test 4 a priori cognition‐WM associations. The following relationships were examined: episodic memory and fornix and hippocampal cingulum integrity; executive function and uncinate fasciculus integrity; visuospatial processing and hippocampal cingulum integrity.ResultIn the linear regression models (Table 2), lower hippocampal cingulum FA and greater hippocampal cingulum RD were each associated with better episodic memory performance. Additionally, lower uncinate fasciculus RD (but not FA) was associated with better executive function performance. In contrast, amyloid positivity (i.e., cDVR > 1.06) was unrelated to any of the cognitive composite scores (all ps > .35).ConclusionMeasures of WM tract integrity account for variability in cognitive performance among cognitively normal individuals, and this association is independent of amyloid burden. Additional analyses are needed to determine whether these microstructural measures reflect general, age‐related markers of neuronal injury vs. alterations related to preclinical AD.

Learning vector quantization model for prediction of cerebral Aβ in non‐demented individuals using plasma biomarkers

AbstractBackgroundCerebral Aβ is the hallmark of the AD in the early therapeutic intervention as well as diagnosis of the disease. Detecting in‐vivo Aβ deposition, however, still have limited accessibility. In this respect, the current study aims to identify plasma markers related to cerebral Aβ status via simple machine learning approach.MethodsPredictability of the candidate plasma markers for cerebral Aβ burden was examined by analyzing 303 non‐demented participants those who had rules based medicine (RMB) and amyloid PET data from the ADNI cohort at baseline visit (83 control and 220 with MCI). Demographic variables (age, gender, education, and APOE status), and 146 of 190 plasma analytes passed quality check were selected as input in learning vector quantization (LVQ) model. The cerebral Aβ burden was measured using PiB PET images. Predictability and importance of variable were calculated using LVQ model.ResultsLVQ model with 10‐cross validation predicted cerebral Aβ status with the 90.67% accuracy (balanced accuracy: 93.14%) in non‐demented people. Based on variable importance analysis, Top‐10 variables above importance ratio above 60 after rescaling were selected: APOE carrier status (100.00), Angiotensin‐Converting Enzyme (ACE, 92.77), Eotaxin‐3 (89.74), Chromogranin A (CgA, 83.61), Brain Natriuretic Peptide (BNP, 79.61), Creatine Kinase‐MB (CK‐MB, 69.61), Monokine Induced by Gamma Interferon (68.26), T Lymphocyte‐Secreted Protein I‐309 (I‐309, 66.89), Matrix Metalloproteinase‐9 (MMP‐9, 64.52), Matrix Metalloproteinase‐9 total (MMP‐9 total, 60.90).ConclusionsOur findings demonstrated that plasma based analytes can predict the cerebral Aβ positivity in non‐demented people. More specifically, ACE is can be a candidate marker for early detection of Aβ deposition in the asymptomatic stage of dementia. Plus, Eoxatain, and CgA can also play a role in AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program(IITP‐2021‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).

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.

Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease.

To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ]42, phosphorylated tau181, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. CSF Aβ42 and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ -0.5). CSF phosphorylated tau181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (R avg ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (R avg < -0.2). CSF Aβ42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.

Test-Retest Variability of Relative Tracer Delivery Rate as Measured by [11C]PiB

PurposeModerate-to-high correlations have been reported between the [11C]PiB PET-derived relative tracer delivery rate R1 and relative CBF as measured using [15O]H2O PET, supporting its use as a proxy of relative CBF. As longitudinal PET studies become more common for measuring treatment efficacy or disease progression, it is important to know the intrinsic variability of R1. The purpose of the present study was to determine this through a retrospective data analysis.ProceduresTest-retest data belonging to twelve participants, who underwent two 90 min [11C]PiB PET scans, were retrospectively included. The voxel-based implementation of the two-step simplified reference tissue model with cerebellar grey matter as reference tissue was used to compute R1 images. Next, test-retest variability was calculated, and test and retest R1 measures were compared using linear mixed effect models and a Bland-Altman analysis.ResultsTest-retest variability was low across regions (max. 5.8 %), and test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and a negligible bias (0.69±3.07 %).ConclusionsIn conclusion, the high precision of [11C]PiB R1 suggests suitable applicability for cross-sectional and longitudinal studies.

Translating amyloid PET of different radiotracers by a deep generative model for interchangeability

It is challenging to compare amyloid PET images obtained with different radiotracers. Here, we introduce a new approach to improve the interchangeability of amyloid PET acquired with different radiotracers through image-level translation. Deep generative networks were developed using unpaired PET datasets, consisting of 203 [11C]PIB and 850 [18F]florbetapir brain PET images. Using 15 paired PET datasets, the standardized uptake value ratio (SUVR) values obtained from pseudo-PIB or pseudo-florbetapir PET images translated using the generative networks was compared to those obtained from the original images. The generated amyloid PET images showed similar distribution patterns with original amyloid PET of different radiotracers. The SUVR obtained from the original [18F]florbetapir PET was lower than those obtained from the original [11C]PIB PET. The translated amyloid PET images reduced the difference in SUVR. The SUVR obtained from the pseudo-PIB PET images generated from [18F]florbetapir PET showed a good agreement with those of the original PIB PET (ICC = 0.87 for global SUVR). The SUVR obtained from the pseudo-florbetapir PET also showed a good agreement with those of the original [18F]florbetapir PET (ICC = 0.85 for global SUVR). The ICC values between the original and generated PET images were higher than those between original [11C]PIB and [18F]florbetapir images (ICC = 0.65 for global SUVR). Our approach provides the image-level translation of amyloid PET images obtained using different radiotracers. It may facilitate the clinical studies designed with variable amyloid PET images due to long-term clinical follow-up as well as multicenter trials by enabling the translation of different types of amyloid PET.

In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborization are characteristic and can be quantified in vivo, with [11C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive supranuclear palsy – Richardson's Syndrome (PSP-RS; n = 22) and amyloid-negative (determined by [11C]PiB PET) Corticobasal Syndrome (Cortiobasal degeneration, CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [11C]UCB-J non-displaceable binding potential (BPND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [11C]UCB-J BPND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

Serial position effects in the Logical Memory Test: Loss of primacy predicts amyloid positivity.

Story recall is a frequently used neuropsychological test of episodic memory with clinical populations and for screening participants in drug trials for Alzheimer's disease. However, it is unclear at this stage which underlying mechanisms confer the test its sensitivity. In this paper, we examined serial position effects, that is, better recall for items learned early and late on a list, in story recall, and their usefulness to predict early changes associated with neurodegenerative markers. We analysed data from the Wisconsin Registry for Alzheimer's Prevention. First, we tested whether serial position effects were present in story recall (measured with the Wechsler Memory Scale Logical Memory Task; LMT) across individuals who were classified as cognitively unimpaired - stable, cognitively unimpaired - declining, or as having mild cognitive impairment (MCI). Our results showed clear serial position effects for all groups, except for delayed recall among individuals with MCI, where no primacy effect was observed. Second, we tested whether loss of primacy from immediate to delayed recall was associated with amyloid burden (as measured with PiB PET) in individuals who were cognitively unimpaired at baseline. We found that more primacy loss predicted amyloid positivity, above and beyond the LMT total score. This report is the first to show that loss of primacy between immediate and delayed story recall is associated with amyloid burden.

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.

Predictive value of visually rated tau PET imaging for amyloid status, atrophy, and syndromic diagnosis across a spectrum of neurodegenerative phenotypes

AbstractBackgroundWe aimed to investigate the utility of qualitative visual rating of 18F‐flortaucipir tau PET to predict amyloid status, neurodegeneration and syndromic diagnosis across a range of phenotypes associated with underlying Alzheimer disease (AD) and non‐AD neuropathologies.MethodFTP PET, PiB PET, and high resolution T1 MRI scans were rated independently by visual inspection by two raters blinded to clinical diagnosis in n=118 subjects, a subset of whom had clinical diagnoses of amnesic MCI/dementia (n=26), posterior cortical atrophy (n=12), logopenic primary progressive aphasia (n=8), nonfluent PPA (n=7), semantic PPA (n=5), corticobasal syndrome (n=7), behavioral variant frontotemporal dementia (n=2), progressive supranuclear palsy (n=2), dementia with Lewy bodies (n=6), Parkinson disease (n=11), or control (n=20). Scans were classified based on level of uptake [no elevation, questionable or mild elevation, substantial elevation] and distribution of uptake [suggestive of typical AD, limbic predominant AD, hippocampal sparing AD, FTLD, or indeterminate]. PiB PET and MRI scans were rated with respect to level and distribution of uptake/atrophy.Result41/42 subjects with FTP scans classified with substantially elevated signal had PiB scans classified with elevated amyloid, versus 7/11 subjects with FTP classified as having questionable/mild elevation in a distribution suggesting AD, 1/30 with questionable/mild elevation in a distribution suggesting FTLD, 0/9 with questionable/mild elevation in an indeterminate distribution, and 1/26 classified with no elevation in FTP signal. Similarly, 41/42 subjects with FTP classified as having substantially elevated signal had MRI scans classified as having atrophy suggesting neurodegeneration, versus 44/50 subjects with FTP classified as having questionable/mild elevation and 14/26 with no elevation in signal. FTP scans were read to be suggestive of AD‐typ in 21/26 subjects with an amnesic syndrome, suggestive of AD‐hs in 16/20 subjects with lvPPA or PCA, and suggestive of FLTD in 14/23 subjects with bvFTD, nvPPA, svPPA, CBS, or PSP.ConclusionVisually rated tau PET imaging reliably predicts amyloid status and atrophy suggesting neurodegeneration in subjects with substantially elevated signal reflecting neocortical tau. Distribution helps both to determine likelihood of underlying AD neuropathology in cases with questionable/mild signal elevation, and in some cases to predict syndromic diagnosis within the spectrums of AD and FTLD.

Associations between an abbreviated CAIDE score and amyloid chronicity

AbstractBackgroundEfforts to quantify dementia risk have led to the development of indices that include health factors, like the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) index. Prior studies demonstrate that higher CAIDE is associated with cognitive decline and neurodegeneration. Few studies have analyzed the association between CAIDE and Alzheimer’s disease (AD)‐related pathophysiology, like beta‐amyloid. Recent studies suggest that duration of beta‐amyloid positivity (amyloid chronicity) is associated with cognitive decline. It is unclear whether health factors contribute to the onset of beta‐amyloid accumulation. This study examines the relationship between the three cardiovascular components of the CAIDE score and amyloid chronicity as assessed by [C‐11]PiB PET imaging.MethodParticipants (n=272; Table 1) from the Wisconsin Registry for Alzheimer’s Prevention were included in this study based on the availability of PiB‐PET imaging data, APOE information, and cardiovascular CAIDE components (total cholesterol, BMI, and systolic blood pressure; CAIDE range 0‐3). Based on observed stability of CAIDE scores (Figure 1), a within‐person average was used in linear regression models assessing whether average CAIDE was associated with amyloid chronicity (calculated as last CAIDE assessment age – estimated age PiB(+)) or estimated age of PiB(+) onset (sensitivity analysis).ResultThe median average CAIDE was 0.4 (1st and 3rd quartiles = 0 and 1 CAIDE, respectively). The mean(SD) age of last PiB scan and last CAIDE ages were 66.55(6.74) and 66.53(6.45), respectively. After adjusting for covariates (education, sex, APOE status, last scan age), CAIDE score was not associated with amyloid chronicity (beta=‐0.47; p=0.74). Sensitivity analyses examining amyloid onset and amyloid positivity since last scan were consistent with our primary analysis. In secondary analyses, we found that CAIDE did not modify associations between APOE status and amyloid chronicity at time of last CAIDE (beta=‐0.28; p=0.87; see Table 2 for full model output).ConclusionOur results suggest that peripheral measures of vascular health do not relate to beta‐amyloid duration in a relatively healthy sample. These results add to recent findings suggesting the independent pathways leading to cognitive decline for vascular factors and amyloid. In the future, we will probe the relationship between health factors, AD‐related pathology, and cognition.

A tau PET study of primary age‐related tauopathy in healthy volunteers

AbstractBackgroundThe term “primary age‐related tauopathy” (PART) was recently introduced to describe a pathology that is commonly observed in the brain of aged individuals. Symptoms in persons with PART usually range from normal cognition to amnesia. The aim of the study is to explore the tau aggregates accumulation in the brain of healthy volunteers by PET with [18F]PM‐PBB3 ( [18F]APN‐1607).MethodFifty‐three healthy individuals (28 men and 25 women ranging in age from 23 to 79 years with a mean of 60) without any history of psychiatric and neurological diseases participated in this study. All subjects underwent neurological examination, cognitive tests, brain MRI, [11C]PiB PET (Aβ imaging), and [18F]PM‐PBB3 PET. [11C]PiB PET images (50‐70 min) was visually assessed. An automated analysis of the volumes of interest in [18F]PM‐PBB3 images (90‐110 min) was performed using the PNEURO module in the PMOD software. Standardized uptake value ratio (SUVR) values were obtained using the cerebellar cortex as a reference region. Pearson correlation analysis was performed between [18F]PM‐PBB3 SUVR and age.ResultNeurological examination revealed no significant finding except for hand tremors in one subject. Cognitive tests were normal in all subjects. Two men were Aβ positive and excluded from the following analysis. There was a positive correlation between age and tau PET signal in the parahippocampus (r = 0.30, P &lt; 0.03), fusiform gyrus (r = 0.41, P &lt; 0.003), and middle and inferior temporal cortex (r = 0.28, P &lt; 0.05) of 51 subjects. No positive correlation between age and [18F]PM‐PBB3 SUVR was found in any other brain regions.ConclusionThe present result supports the concept of PART and the detectability of PART‐type tau deposits by PET with [18F]PM‐PBB3.

Racial comparisons of MRI and PiB PET in acute stroke

AbstractBackgroundStroke and Alzheimer disease share risk factors and often co‐occur, and both have been reported to have a higher prevalence in African‐Americans. However, the interaction of race, stroke, and Alzheimer disease has not been established.MethodWe compared MRI and PiB PET biomarkers of non‐demented participants with and without acute ischemic stroke (total n=243, age 65‐101), with a focus on comparing African‐Americans (n=42 with stroke, n=84 without) to Non‐Hispanic Whites (n=39 with stroke, n=78 without). Our assessment included radiologic reads of the number of large infarcts, small infarcts, microbleeds, and leukoaraiosis; a PET measure of amyloid binding; quantitative measures of hippocampal volume and white matter hyperintensities; and longitudinal Mini Mental State Exam (MMSE) scores. Statistical analysis used logistic regression models to predict each biomarker using race and stroke status, while controlling for age, family history, APOE4, education, sex, and high blood pressure.ResultPiB PET did not differ significantly by stroke status or by race, with 23.6% of participants being classified as amyloid positive (Figure 1). As expected in stroke, the acute stroke participants were more likely to have large infarcts, small infarcts, microbleeds, and non‐zero Fazekas scores. MMSE showed racial differences at baseline (mean 26.8 for African‐Americans, 27.9 for Non‐Hispanic Whites, p=0.03), but not longitudinally. Overall, African‐Americans were more likely to have microbleeds (32.8% vs 22.6%, p=0.04). Within the stroke group African‐Americans were more likely to have small infarcts (75.6% vs 56.8%, p=0.049). Combined, African‐Americans were also more likely to have more than 5 microbleeds ‐ the cutoff for many Alzheimer clinical trials (15.2% vs 9.6%, p=0.04).ConclusionPreclinical Alzheimer disease does not appear to be a risk factor for stroke and did not differ by race in our sample. Standard clinical MRI measures differed by stroke status, but showed few racial differences. The observed lower MMSE scores in African‐Americans has been reported previously and may arise for a variety of reasons. In individuals with stroke, African‐Americans may have more severe pathology as evidenced by greater numbers of small infarcts and microbleeds. African‐Americans may be more likely to be excluded from Alzheimer disease clinical trials due to having 5 or more microbleeds.

Cognitive status, brain amyloid pathology, and neurodegeneration are associated with altered white matter microstructure

AbstractBackgroundBrain amyloid (AB) and neurodegeneration (assessed using PET and MRI) are key AD pathology biomarkers, particularly during transitions from cognitively unimpaired (CU) to cognitively impaired (CI) states. Importantly, the role of brain white matter microstructural measures in these changes, such as those derived from neurite orientation dispersion and density imaging (NODDI), are poorly understood. We explored roles of cognitive status, brain amyloid pathology, and neurodegeneration on NODDI Free Water (FW), a potential neuroinflammation biomarker.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N=74, Table 1) underwent neuropsychological assessment, T1/NODDI MRI, and PiB PET. Participants were adjudicated as cognitively impaired (MCI or AD) or unimpaired using NIA‐AA criteria. T1 MRI were processed (FreeSurfer v5.3) to generate regions of interest (ROIs). An “AD‐signature” cortical thickness value was calculated, and thresholded to classify participants as neurodegeneration‐positive (N+) or ‐negative (N‐). A set of AD‐sensitive cortical ROIs was used to extract mean PET signal, which was thresholded to adjudicate AB positivity (AB‐/AB+). NODDI was processed to yield parameter maps using AMICO; mean isotropic volume fraction (FW) was calculated over a set of white matter tract ROIs. A two‐way ANOVA/ANCOVA (covariates: age, sex, education) assessed effects of neurodegeneration and AB on FW (N+/N‐ x AB+/AB‐), and a two‐way ANOVA/ANCOVA assessed effects of cognitive impairment and AB on FW (CU/CI x AB+/AB‐).ResultWe first examined effects of neurodegeneration and AB on NODDI FW. We found a significant main effect of neurodegeneration (p=.042), such that N+ had higher FW; this was marginal after adjustment (p=.07). We also observed a significant main effect of AB (p&lt;.001; adjusted p=.012), with AB+ having higher FW. There was no significant interaction. We next explored how cognitive status and AB interacted on FW. We found a significant main effect of cognitive impairment, with CI having higher FW (p=.018; adjusted p=.013). We also found an interaction between diagnosis and AB (p=.037; adjusted p=.044) such that among AB+ individuals, presence of CI related to increased FW (Figure 1).ConclusionNODDI FW increases were significantly affected by the presence of neurodegeneration, AB positivity, and cognitive impairment.

Association of plasma neurofilament light chain (pNfL) with neuroimaging markers of neurodegeneration and cerebrovascular disease

AbstractBackgroundCerebrospinal fluid (CSF) concentrations of neurofilament light chain (NfL) have previously been reported to be associated with severity of white matter hyperintensity (WMH) (Bjerke, M. et al. 2014; Jonsson, M. et al. 2010; Sjogren, M. et al. 2001). CSF NfL level has also been reported to be significantly increased in vascular dementia (VaD) patients compared with cognitively normal controls (NCI) (Zhao, Xin et al. 2019). However, plasma NfL (pNfL) in VaD subjects and its association with WMH or other magnetic resonance imaging (MRI) markers of cerebrovascular disease (CeVD) have yet to be investigated. The objectives of this study were to (1) examine whether pNfL levels differ between diagnostic groups (NCI, cognitive impairment no dementia [CIND], Alzheimer’s disease [AD] and VaD, and (2) assess the association between pNfL with neuroimaging markers (amyloid PET, MRI) and cognition (Mini‐Mental State Examination [MMSE] scores).MethodThis study included participants who were clinically diagnosed as NCI (n=43), CIND (n=99), VaD (n=22) or AD (n=44). Presence of significant CeVD burden (CeVD+) was defined as occurrence of cortical infarcts and/or ≥2 lacunes, and/or confluent white matter lesions on MRI. Presence of neurodegeneration (N+) was determined by medial temporal atrophy scores. Presence of elevated brain amyloid (A+) was determined by visual assessment of amyloid PET, performed with either PiB (n=178) or NAV (n=30) ligand. pNfL was measured on the Simoa‐HD 1 platform.ResultpNfL level was significantly increased in VaD and AD patients compared with NCI. Across all participants, pNfL was higher in CeVD+ or N+ groups. pNfL was associated with WMH (rho=0.304, p&lt;0.001) and lacunes (rho=0.221, p&lt;0.001), but not cortical infarcts. There was no difference in pNfL level between the A+ and A‐ groups. Similarly, pNfL did not correlate with SUVR measured by PiB or NAV amyloid PET tracer. Correlation between pNfL and MMSE was moderate but significant (rho=‐0.340, p&lt;0.001). pNfL was independently associated with WMH and worse performance in MMSE.ConclusionpNfL level was increased in both VaD and AD. pNfL was associated with cognitive decline and WMH.

Associations between amyloid‐β, white matter disease, functional brain networks, and mobility function: Possible indicators of reserve and resilience

AbstractBackgroundUndetected AD pathology in cognitively normal older adults may increase risk for mobility decline by both increasing white matter pathology and directly interfering with functional networks through Aβ deposition.MethodsThirty‐one cognitively normal older adults (75.01 ± 4.15 y, 35.5% female) enrolled in the Brain Networks and Mobility Function (B‐NET) study received PiB PET and MRI. A global cortical PiB average for each participant was calculated by coregistering PET to MRI using Freesurfer v5.6 to generate masks and thresholding at 1.21 to create PiB positivity groups (PiB‐ = 16, PiB+ = 15). White matter hyperintensity (WMH) volume was calculated with the Lesion Segmentation Toolbox (LST) implemented in SPM12. Mobility function was assessed using the expanded Short Physical Performance Battery (eSPPB), a 4‐meter walk, and a 400‐meter walk. Cognitive measures included the Montreal Cognitive Assessment (MOCA) and Digit Symbol Substitution Task (DSST). Associations were explored using linear regression, correcting for age, sex, and BMI in the fully adjusted mobility model while age, sex, and education were used in the fully adjusted cognition and WMH model.ResultsPiB+ individuals had significantly faster 4‐meter gait speed (p&lt;0.05) and a trend for higher DSST (p=0.052). These associations were independent of WMH volume. PiB+ individuals also had significantly higher total (p&lt;0.05) and motor WMH (p&lt;0.05).ConclusionsThe observation that PiB+ individuals had better physical function than PiB‐ was unexpected given existing literature showing associations between regional Aβ volume and slower gait speed. It was also unexpected given that the PiB+ group had higher WMH volume, which is associated with slower gait speed. The current sample, which includes primarily individuals with good physical and cognitive function, may represent a resilient phenotype. Continued recruitment of more diverse participants with lower physical function will be an important addition to this sample. Future analyses will allow for the inclusion of APOE and an increased sample size. Whole‐brain functional connectivity will also be assessed in this cohort using graph‐theory based methods.

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.