AV-1451 PET Research Articles

CNTN5 is associated with disease risk and pathology throughout the Alzheimer's disease continuum.

Contactins are a family of molecules that are involved in neuronal development. Contactin 5 (CNTN5) is a neuronal membrane protein that contributes to axonal targeting, synaptic formation and plasticity. A GWAS performed in a population isolate from Eastern Canada identified a polymorphism in the CNTN5 gene (rs1461684_G) which is associated with increased risk of developing Alzheimer's disease (AD). In order to further characterize the role of CNTN5 in AD, we used two cohorts (the "at-risk" pre-symptomatic PREVENT-AD and the symptomatic ROSMAP) to examine the association of CNTN5 genotype and protein levels with pathological hallmarks and clinical manifestations of AD. In the PREVENT-AD cohort, [18F]-AV1451 PET was used to measure Tau burden, Olink's primer extension assay was used to measure CNTN5 in plasma and CSF and ELISAs were used for Tau, Phospho Tau, and amyloid CSF levels. Participants were followed for at least 4 years. In the autopsied-confirmed ROSMAP cohort, Aß load and NFT density in the cortex were measured with immunocytochemistry, and cognition was assessed with the Mini-Mental State Examination (MMSE). In the ROSMAP cohort participants were followed throughout most of their adult life, until death. Homozigotes CNTN5 G variant had a 58% lower chance of developing cognitive decline than non-carriers and heterozygous subjects (p=0.033) (Fig 1a). Carriers of the GG variant showed less decline in MMSE scores compared to the other genotypes (p=0.042) (Fig 1b). CSF CNTN5 levels were higher in follow-up visits 12 (p=0.018), 24 (p=0.013) and 48 (p<0.001) months compared to baseline (Fig 2) and, were significantly higher in Controls compared to AD subjects (p<0.001) (Fig 3). CSF CNTN5 was positively correlated with PET TAU burden in the entorhinal cortex (p=0.029), with CSF Total Tau (p<0.001), Phospho Tau (p<0.001), Aß1-42(p=0.018) and Aß 1-40 (p=0.002) (Fig 4). There was no correlation between Plasma and CSF CNTN5 levels (p =0.37). There are no association between CNTN5 genotype and CERAD or Braak stages. These results show that the rs146168 variant of CNTN5 plays a role in the risk of developing AD and that CNTN5 CSF levels are strongly correlated with AD pathology, especially in the pre-symptomatic phase of the disease.

Does [18F]FDG and [18F]AV1451 PET predict neurodegeneration?

AbstractBackground[18F]FDG PET is a well‐established and valuable biomarker in the assessment of neurodegenerative disorders, with high diagnostic utility, wide accessibility, and relatively low costs. Recent advances in PET imaging technology now allow for the in vivo exploration of tau deposition. However, it is still being debated which of [18F]FDG PET or [18F]AV1451 PET better predicts neurodegeneration. This study aimed to evaluate [18F]FDG PET and [18F]AV1451 PET imaging in predicting grey matter atrophy in patients with cognitive impairment.Method190 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.3 years, SD = 8.04) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, [18F]AV1451 and [18F]FDG PET scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within the medial temporal lobe. Whole brain grey matter volumes were obtained from processed data from ADNI. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere was a significant negative association between [18F]AV1451 uptake in the medial temporal lobe and whole brain grey matter volume (r = ‐0.288, p = 0.001). A stronger positive relationship was identified between medial temporal lobe [18F]FDG uptake and whole brain grey matter volume (r = 0.444, p &lt; 0.001).ConclusionThis study demonstrated that regional FDG and tau tracer uptake in patients with cognitive impairment both display a significant relationship with total grey matter volume. Whilst both tracers show utility in predicting a patient’s level of neurodegeneration, glucose metabolism as indicated by [18F]FDG PET appears to have a closer relationship to grey matter atrophy than PET markers of tau deposition.

Bilingualism is associated with lower cognitive decline and with lower levels of AD biomarkers in a cognitively unaffected cohort

AbstractBackgroundSpeaking two or more languages has been shown to contribute to cognitive reserve and to delay the onset of Alzheimer’s disease (AD). However, little is known about the effect of bilingualism on the progression of AD biomarkers. In this study, we intended to investigate the effect of bilingualism on cognitive scores and on AD biomarkers in a cohort of cognitively unaffected individuals.MethodWe analyzed data from participants of the PREVENT‐AD cohort. This cohort comprises cognitively normal participants over the age of 55 who have a first degree relative with AD. Cognition was assessed with the RBANS scale, Tau burden was measured with [18F]‐AV1451 PET, and CSF biomarkers were measured with Innotest’s enzyme‐linked immunosorbent assay kit (Fujirebio, Ghent, Belgium). Analyses were performed comparing participants who speak one, two or three languages and comparing participants who speak one or more than one language.ResultA total of 327 participants were included, with 89 that speak one language, 195 that speak two languages, and 43 that speak three languages. We found that participants who speak more than one language have significantly higher attention scores (p=0.041) (Fig. 1a) and total RBANS scores (p=0.021) (Fig 1b) than participants who speak only one language. Participants who speak two languages have a lower tau burden in the entorhinal cortex than participants who speak one language (p=0.047) (Fig. 2). For total Tau, participants who speak more than one language have lower CSF levels than participants who speak one language. This difference increases over time and becomes statistically significant on follow up visits 36 months (p=0.049) and 48 months (p= 0.031) (Fig 3a). Participants who speak more than one language have lower CSF levels of phospho‐Tau (p= 0.017) (Fig 3b), and neurofilament light (p=0.041)(Fig 3c) compared to participants who speak one language.ConclusionOur results show that bilingualism is associated not only with less cognitive decline, but also with lower levels of AD biomarkers in pre‐symptomatic AD.

Influence of common reference regions on regional tau patterns in cross-sectional and longitudinal [18F]-AV-1451 PET data

Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment.

The roles of amyloid-β and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-β in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.

Leveraging molecular biomarkers to make the common diagnosis in the uncommon patient

Background and purposeThe factors that predispose to relapse in patients recovering with autoimmune encephalitis (AE) are largely unknown, complicating efforts to distinguish patients with resurgent symptoms who may benefit from additional immune-modulating therapies from those with other causes of impairment. MethodsWe report a patient with AE with leucine-rich glioma-inactivated 1 autoantibodies with a typical presentation, but atypical course complicated by treatment-refractory psychoses and progressive cognitive decline. We leveraged emergent molecular biomarkers, including [18F]florbetapir (amyloid) and [18F]flortaucipir AV45 (tau) PET neuroimaging, to evaluate for common neurodegenerative causes of impairment. The patient was followed until death and a brain autopsy performed. ResultsNo evidence of active inflammation was observed on neuroimaging or cerebrospinal fluid analyses in our patient with resurgent, treatment-refractory cognitive decline. [18F]Florbetapir and [18F]flortaucipir retention were increased in cerebral cortices in a pattern consistent with symptomatic Alzheimer's disease. Immunomodulatory therapies were stopped, and appropriate counseling provided to the patient and family. The patient died 2.4 months following [18F]flortaucipir PET neuroimaging. Brain autopsy confirmed changes typical of Alzheimer's disease without evidence of active inflammation or sequelae of AE, establishing Alzheimer's disease as the likely cause of resurgent symptoms in this patient. ConclusionsSymptoms of age-related neurodegenerative illnesses may emerge following AE, particularly in older patients in whom neurodegenerative dementing illnesses are more common. Molecular biomarkers may aid in the evaluation of treatment-refractory patients with resurgent symptoms and signs, influencing management.

Validation of the Alzheimer Disease Dementia Conversion-Related Pattern as an ATN Biomarker of Neurodegeneration.

To determine whether the Alzheimer disease (AD) dementia conversion-related pattern (ADCRP) on [18F]FDG PET can serve as a valid predictor for the development of AD dementia, the individual expression of the ADCRP (subject score) and its prognostic value were examined in patients with mild cognitive impairment (MCI) and biologically defined AD. A total of 269 patients with available [18F]FDG PET, [18F]AV-45 PET, phosphorylated and total tau in CSF, and neurofilament light chain in plasma were included. Following the AT(N) classification scheme, where AD is defined biologically by in vivo biomarkers of β-amyloid (Aβ) deposition ("A") and pathologic tau ("T"), patients were categorized to the A-T-, A+T-, A+T+ (AD), and A-T+ groups. The mean subject score of the ADCRP was significantly higher in the A+T+ group compared to each of the other group (all p < 0.05) but was similar among the latter (all p > 0.1). Within the A+T+ group, the subject score of ADCRP was a significant predictor of conversion to dementia (hazard ratio, 2.02 per z score increase; p < 0.001), with higher predictive value than of alternative biomarkers of neurodegeneration (total tau and neurofilament light chain). Stratification of A+T+ patients by the subject score of ADCRP yielded well-separated groups of high, medium, and low conversion risks. The ADCRP is a valuable biomarker of neurodegeneration in patients with MCI and biologically defined AD. It shows great potential for stratifying the risk and estimating the time to conversion to dementia in patients with MCI and underlying AD (A+T+). This study provides Class I evidence that [18F]FDG PET predicts the development of AD dementia in individuals with MCI and underlying AD as defined by the AT(N) framework.

Synergistic Effect of Serum Homocysteine and Diabetes Mellitus on Brain Alterations.

Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11C] Pittsburgh Compound B (PiB) PET, [18F] AV-1451 PET, and brain MRI. The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer's disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome

IntroductionAdults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. MethodsA total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL < 13.3), subthreshold A+ (13.3 ≤ AβL < 20) and conventionally A+ (AβL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. ResultsA large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AβL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DiscussionThese results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer’s disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer’s disease.

Identifying and predicting heterogeneity in cognitive decline among individuals with prodromal Alzheimer's disease using a latent class analysis

AbstractBackgroundIndividuals with prodromal Alzheimer’s disease (AD) show heterogeneity in their rates of cognitive decline, which is problematic for measuring (therapeutic) effects on cognition. We aimed to identify subgroups with homogeneous cognitive trajectories among individuals with prodromal AD in two large independent cohorts, and investigate which clinical and/or biological AD risk factors predict progression rate.MethodIndividuals with an abnormal amyloid marker (determined by either CSF Aβ‐42 levels or Florbetaben/Flutametamol/Florbetapir‐AV45 PET imaging) and mild cognitive impairment who had longitudinal cognitive data available were selected from the Amsterdam Dementia Cohort and ADNI (N=340, age =71.5±8.4, 43% female). We performed latent class mixed models (LCMM) to identify subgroups based on similarity of their trajectories on the Mini‐Mental State Examination (MMSE), and performed mixture modelling using individual MMSE slopes to validate those subgroups. We compared subgroups on baseline age, sex, years of education, ApoE‐e4 status, CSF tau and phosphorylated tau (p‐tau) and hippocampal volume using univariate logistic regression, and subsequently performed stepwise logistic regression with backward elimination to identify which baseline characteristics best predicted progression.ResultParticipants had 2.3±1.8 repeated assessments and a follow‐up of 2.3±1.6 [range=1‐8] years. LCMM identified three subgroups of MMSE progression, which were confirmed by mixture modelling: Group 1 (n=303, 88%) showing slowest progression (i.e. average 0.7 [range=0.4–1.9] points annual decline on MMSE); Group 2 (n=30, 10%) intermediate progression (average 2.6 [range=1.9–4.2] points annual decline on MMSE) and Group 3 (n=7, 2%) showing fastest progression (average 4.7 [range=3.3–6.2] points annual decline on MMSE) (Figure 1). No effects on progression were observed for age, sex, education and ApoE‐e4 (Table 1). Compared to individuals who slowly progressed, those with intermediate‐to‐fast progression had higher tau (OR=1.01, 95%CI=[1.01‐1.02], p&lt;.001) and p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p&lt;.001) levels and lower hippocampal volume (OR=0.57, 95%CI=[.37‐.84], p=.006) at baseline. The model including both p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p&lt;.001) and hippocampal volume (OR=0.55, 95%CI=[.34‐.85], p=.01) best predicted fast progression.ConclusionAmong individuals with prodromal AD, we identified three subgroups with different rates of decline on the MMSE, and demonstrated that baseline neurodegeneration markers were associated with faster decline. These findings have practical implications for clinical trial enrollment and predicting disease progression.

Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy.

We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. Nondisplaceable binding potential (BPND ) for each ligand was quantified in 83 regions of interest (ROIs). The [11 C]PK11195 and [18 F]AV-1451 BPND values were correlated across all regions. The spatial distributions of [11 C]PK11195 and [18 F]AV-1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients' clinical severity (using the PSP rating scale). Regional [11 C]PK11195 and [18 F]AV-1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11 C]PK11195 and [18 F]AV-1451 components' loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP. ANN NEUROL 2020;88:1194-1204.

β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies

In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype. We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+. A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype. Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB. This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

PET Tau Imaging and Motor Impairments Differ Between Corticobasal Syndrome and Progressive Supranuclear Palsy With and Without Alzheimer's Disease Biomarkers.

Introduction: Frontotemporal lobar degeneration (FTLD)-related syndrome includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). PSP is usually caused by a tauopathy but can have associated Alzheimer's disease (AD) while CBS can be caused by tauopathy, transactive response DNA binding protein 43 kDa, or AD pathology. Our aim was to compare the parkinsonian syndromes presenting without AD biomarkers (CBS/PSP-non-AD) to parkinsonian syndromes with AD biomarkers (CBS/PSP-AD).Materials and Methods: Twenty-four patients [11 males, 13 females; age (68.46 ± 7.23)] were recruited for this study. The whole cohort was divided into parkinsonian syndromes without AD biomarkers [N = 17; diagnoses (6 CBS, 11 PSP)] and parkinsonian syndromes with AD biomarkers [N = 7; diagnoses (6 CBS-AD, 1 PSP-AD)]. Anatomical MRI and PET imaging with tau ligand [18F]-AV1451 tracer was completed. Cerebrospinal fluid analysis or [18F]-AV1451 PET imaging was used to assess for the presence of AD biomarkers. Progressive supranuclear palsy rating scale (PSPRS) and unified Parkinson's disease rating scale (UPDRS) motor exam were implemented to assess for motor disturbances. Language and cognitive testing were completed.Results: The CBS/PSP-non-AD group [age (70.18 ± 6.65)] was significantly older (p = 0.028) than the CBS/PSP-AD group [age (64.29 ± 7.32)]. There were no differences between the groups in terms of gender, education, years of disease duration, and disease severity as measured with the Clinical Dementia Rating scale. The CBS/PSP-non-AD group had significantly lower PET Tau Standard Volume Uptake Ratio (SUVR) values compared to the CBS/PSP-AD group in multiple frontal and temporal areas, and inferior parietal (all p < 0.03). The CBS/PSP-non-AD group had significantly higher scores compared to the CBS/PSP-AD group on PSPRS (p = 0.004) and UPDRS motor exam (p = 0.045). The CBS/PSP-non-AD group had higher volumes of inferior parietal, precuneus, and hippocampus (all p < 0.02), but lower volume of midbrain (p = 0.02), compared to the CBS/PSP-AD group.Discussion: The CBS/PSP-non-AD group had higher motor disturbances compared to the CBS/PSP-AD group; however, both groups performed similarly on neuropsychological measures. The AD biomarker group had increased global uptake of PET Tau SUVR and lower volumes in AD-specific areas. These results show that the presenting phenotype of CBS and PSP syndromes and the distribution of injury are strongly affected by the presence of AD biomarkers.

Improving Choroid Plexus Segmentation in the Healthy and Diseased Brain: Relevance for Tau-PET Imaging in Dementia.

Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer's disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n = 19), 2) young healthy subjects (n = 20), and 3) patients with AD (n = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm's performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer's Disease Neuroimaging Initiative (n = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance of accurate ChP segmentation, total AV1451 (tau) PET binding to ChP was measured in 108 MCI and 32 AD patients. GMM was able to reveal the higher AV1451 binding to ChP in AD compared with MCI. Our results provide evidence for the utility of the GMM in accurately segmenting ChP and show its clinical relevance in AD. Future structural and functional studies of ChP will benefit from GMM's accurate segmentation.

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological “signatures” of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

Genome-wide Network-assisted Association and Enrichment Study of Amyloid Imaging Phenotype in Alzheimer's Disease.

The etiology of Alzheimer's disease remains poorly understood at the mechanistic level, and genome-wide network-based genetics have the potential to provide new insights into the disease mechanisms. The study aimed to explore the collective effects of multiple genetic association signals on an AV-45 PET measure, which is a well-known Alzheimer's disease biomarker, by employing a network assisted strategy. First, we took advantage of a dense module search algorithm to identify modules enriched by genetic association signals in a protein-protein interaction network. Next, we performed statistical evaluation to the modules identified by dense module search, including a normalization process to adjust the topological bias in the network, a replication test to ensure the modules were not found randomly , and a permutation test to evaluate unbiased associations between the modules and amyloid imaging phenotype. Finally, topological analysis, module similarity tests and functional enrichment analysis were performed for the identified modules. We identified 24 consensus modules enriched by robust genetic signals in a genome-wide association analysis. The results not only validated several previously reported AD genes (APOE, APP, TOMM40, DDAH1, PARK2, ATP5C1, PVRL2, ELAVL1, ACTN1 and NRF1), but also nominated a few novel genes (ABL1, ABLIM2) that have not been studied in Alzheimer's disease but have shown associations with other neurodegenerative diseases. The identified genes, consensus modules and enriched pathways may provide important clues to future research on the neurobiology of Alzheimer's disease and suggest potential therapeutic targets.

Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes.

Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration. 38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N=13) and low (N=13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison. Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p=0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p=1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p=0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers. There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration. Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.

Sex-specific norms for verbal memory tests may improve diagnostic accuracy of amnestic MCI.

To examine whether the use of sex-specific norms and cut scores to identify memory impairment improves diagnostic accuracy of amnestic mild cognitive impairment (aMCI) compared to non-sex-specific (typical) norms/cut scores given the female advantage in verbal memory. We calculated sex-specific and typical norms/cut scores (age and education specific) for impairment on the Rey Auditory Verbal Learning Test in the Mayo Clinic Study of Aging. Norms/cut scores were applied to 453 women and 532 men from the Alzheimer's Disease Neuroimaging Initiative. We compared sex differences in rates of aMCI (Jak/Bondi criteria) for sex-specific vs typical norms/cut scores. Using sex-specific cut scores as the true condition and typical cut scores as the predicted condition, we categorized participants as true positives (TPs), false positives (FPs), true negative (TNs), or false negative (FNs). In cross-sectional analyses within sex, we compared positivity rates of CSF hyperphosphorylated tau/β-amyloid (Aβ) and cortical Aβ deposition ([18F]AV45 PET) and APOE ε4 frequency among diagnostic comparison groups. The frequency of aMCI was higher in men when using typical norms/cut scores. Using sex-adjusted norms/cut scores led to the identification of 10% FNs (missed aMCI cases) among women and 10% FPs among men. Biomarker analyses supported the hypothesis that sex-specific diagnostic criteria improves diagnostic accuracy. Biomarkers rates were higher in FNs vs TNs and similar in FNs and TPs. Biomarker rates were lower in FPs vs TPs and similar between FPs and TNs. Results suggest that non-sex-specific aMCI diagnostic criteria led to a 20% diagnostic error rate. Accounting for sex differences in verbal memory performance may improve aMCI classification.

18F]-AV-1451 tau PET imaging in Alzheimer's disease and suspected non-AD tauopathies using a late acquisition time window.

The utility of tau PET imaging in non-Alzheimer's disease (AD) tauopathies like behavioural frontotemporal dementia (bvFTD), which is mainly underlain by TDP-43 or tau pathology, remains debated. We aim to test the hypothesis that [18F]-AV-1451 tau PET using later than usual acquisition times, which have previously been shown in AD to allow to get closer to tracer equilibrium between the reference region and high-binding structures, and could be better suited to the lower affinity of this tracer for the straight tau filaments present in non-AD tauopathies, would allow to detect cortical tau pathology in a fraction of bvFTD patients and in patients with non-fluent primary progressive aphasia (nfPPA, most often underlain by tau pathology). Sixteen AD patients, 11 controls, 7 bvFTD patients (including a carrier of a GRN mutation leading to TDP-43 pathology) and 2 nfPPA patients were included. We compared SUVr obtained at the usual early time window for [18F]-AV-1451 PET acquisition (ET: 80-100min) to a later acquisition window (LT: 190-210min) between groups. Compared with ET, [18F]-AV-1451 LT uptake in AD patients was significantly higher in the temporo-parietal cortex, and lower in subcortical regions. The LT window allowed to detect significantly increased tau binding in the frontal or temporal cortex in 3 bvFTD patients and in the 2 nfPPA patients that was not detectable with ET. The GRN mutation carrier showed no significant increase of tracer binding. [18F]-AV-1451 late acquisition window could allow cortical binding to abnormal tau deposits to be revealed in a subset of bvFTD patients, which may distinguish them from the TDP-43 subtype.

PET Imaging of Neurodegeneration With [18F]AV-1451 PET After Repetitive Traumatic Brain Injury

Abstract INTRODUCTION TBI (traumatic brain injury) is associated with an increased risk of late neurodegeneration in chronic TBI survivors. The underlying pathophysiology of trauma-related neurodegeneration is hypothesized to involve a tauopathy, with p-tau deposited in beta-pleated sheets. Current research focuses on identifying strategies to detect trauma-related neurodegeneration in-Vivo. [F-18]AV-1451, a tau-specific PET radiotracer, may detect hyper-phosphorylated tau deposits in living patients. METHODS Participants with a history of TBI &gt;6 mo prior with concern for cognitive decline with age-matched controls were recruited. Subjects were classified into three groups: few (=3 TBI exposures), intermediate (4–10 exposures), and numerous (&gt;10 exposures). Participants underwent PET imaging with [F-18]AV-1451, and qualitative and semi-quantitative (SUVR) analyses of radiotracer retention were performed. Visual classification of tau positivity (+/−) was performed with absence of established positivity thresholds for [F-18]AV-1451 SUVR values. All subjects underwent neuropsychological evaluation, including measures of processing speed, executive function, and memory. RESULTS Twenty-seven TBI subjects and 7 controls were enrolled. A total of 9 participants were categorized as few, 2 as intermediate, 7 as numerous. All TBI subjects demonstrated impairment on at least one neurocognitive measure, while control subjects had normal neuropsychological test results. Analysis of [F-18]AV-1451 uptake patterns demonstrated evidence of tauopathy in 3 subjects, based on visual reads. Significantly increased [F-18]AV-1451 retention was noted in occipital gray matter, posterior cingulate gyrus, and parietal cortex in these 3 tau (+) TBI subjects compared to 24 TBI subjects visually classified as tau (−) and also normal controls. CONCLUSION Evidence of tauopathy, indicative of trauma-related neurodegeneration, was noted in 3 chronic TBI subjects, all of whom were categorized as numerous (&gt;10) TBI exposures and cognitive deficits on neuropsychological testing. No tau PET [F-18]AV-1451 uptake was noted in control participants or in participants categorized as few or intermediate. The data represent a possible [F-18]AV-1451 PET uptake pattern associated with a clinical neurodegeneration syndrome in repetitive TBI.