Search

Background:Amyloid-β plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but amyloid-β load at prodromal stages of DLB still needs to be elucidated. We investigated amyloid-β load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB.Methods:We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer’s Disease Research Center. Amyloid-β levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVr) was calculated. Global cortical PiB SUVr values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex using ANCOVA. We used multiple linear regression testing for interaction to study the influences of sex andAPOEε4 status on PiB SUVr along the DLB continuum.Results:Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared to CU, global cortical PiB SUVr was higher in DLB (p <0.001) and MCI-LB (p=0.012). The DLB group included the highest proportion of amyloid-β positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVr was higher inAPOEε4 carriers compared toAPOEε4 non-carriers in MCI-LB (pp=0.049). Women had higher PiB SUVr with older age compared to men across the DLB continuum (βeta estimate=0.014,p=0.02).Conclusion:In this cross-sectional study, levels of amyloid-β load was higher further along the DLB continuum. Whereas amyloid-β levels were comparable to cognitively unimpaired individuals in iRBD, a significant elevation in amyloid-β levels was observed in the pre-dementia stage of MCI-LB and in DLB. Specifically,APOEε4 carriers had higher amyloid-β levels thanAPOEε4 non-carriers and women tended to have higher amyloid-β levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

Background and ObjectivesTo determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)–PET tracer retention.MethodsParticipants 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.ResultsForty-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.DiscussionWe 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.

Background and ObjectivesAlthough alpha-synuclein–related pathology is the hallmark of dementia with Lewy bodies (DLB), cerebrovascular and Alzheimer disease pathologies are common in patients with DLB. Little is known about the contribution of these pathologies to neurodegeneration in DLB. We investigated associations of cerebrovascular, β-amyloid, and tau biomarkers with gray matter (GM) volume in patients with probable DLB.MethodsWe assessed patients with probable DLB and cognitively unimpaired (CU) controls with11C-Pittsburgh compound B (PiB) and18F-flortaucipir PET as markers of β-amyloid and tau, respectively. MRI was used to assess white matter hyperintensity (WMH) volume (a marker of cerebrovascular lesion load) and regional GM volume (a marker of neurodegeneration). We used correlations and analysis of covariance (ANCOVA) in the entire cohort and structural equation models (SEMs) in patients with DLB to investigate associations of WMH volume and regional β-amyloid and tau PET standardized uptake value ratios (SUVrs) with regional GM volume.ResultsWe included 30 patients with DLB (69.3 ± 10.2 years, 87% men) and 100 CU controls balanced on age and sex. Compared with CU controls, patients with DLB showed a lower GM volume across all cortical and subcortical regions except for the cuneus, putamen, and pallidum. A larger WMH volume was associated with a lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in patients with DLB. A higher PiB SUVr was associated with a lower volume in the inferior temporal cortex, while flortaucipir SUVr did not correlate with GM volume. SEMs showed that a higher age and absence of theAPOEε4 allele were significant predictors of higher WMH volume, and WMH volume in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex. By contrast, we observed 2 distinct paths for the fusiform cortex, with age having an effect through PiB and flortaucipir SUVr on one path and through WMH volume on the other path.DiscussionPatients with probable DLB have widespread cortical atrophy, most of which is likely influenced by alpha-synuclein–related pathology. Although cerebrovascular, β-amyloid, and tau pathologies often coexist in probable DLB, their contributions to neurodegeneration seem to be region specific.

ObjectiveTo determine the clinical phenotypes associated with the β-amyloid PET and dopamine transporter imaging (123I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB).MethodsPatients with MCI who had at least 1 core clinical feature of DLB (n = 34) were grouped into β-amyloid A+ or A− and 123I-FP-CIT SPECT D+ or D− groups based on previously established abnormality cut points for A+ with Pittsburgh compound B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z score with DaTQUANT 123I-FP-CIT SPECT. Individual patients with MCI-LB fell into 1 of 4 groups: A+D+, A+D−, A−D+, or A−D−. Log-transformed PiB SUVR and putamen z score were tested for associations with patient characteristics.ResultsThe A−D+ biomarker profile was most common (38.2%), followed by A+D+ (26.5%) and A−D− (26.5%). The least common was the A+D- biomarker profile (8.8%). The A+ group was older, had a higher frequency of APOE ε4 carriers, and had a lower Mini-Mental State Examination score than the A− group. The D+ group was more likely to have probable REM sleep behavior disorder. Lower putamen DaTQUANT z scores and lower PiB SUVRs were independently associated with higher Unified Parkinson’s Disease Rating Scale-III scores.ConclusionsA majority of patients with MCI-LB are characterized by low β-amyloid deposition and reduced dopaminergic activity. β-Amyloid PET and 123I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.

ObjectiveIn 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.MethodsWe 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+.ResultsA−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.ConclusionsAlzheimer 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.Classification of evidenceThis 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.

ObjectiveTo characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome.MethodsSeventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [18F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [18F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine β-amyloid positivity.ResultsThe bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was β-amyloid–positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter.ConclusionPatterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.

ObjectiveTo assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.MethodsFrom the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.ResultsForty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010–0.087, p = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006–0.067, p = 0.019) in the inferior temporal cortex after controlling for confounders.ConclusionWe identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.

ObjectiveResearch in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A−) in cognitively unimpaired (CU) older adults.MethodsWe included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B–PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.ResultsHigher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A− but weaker in A− CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.ConclusionsA faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.

ObjectiveTo determine the frequency of high-convexity tight sulci (HCTS) in a population-based sample and whether the presence of HCTS and related features influenced participants' cognitive status and classification within the new Alzheimer-biomarker framework.MethodsWe analyzed 684 participants ≥50 years of age who were enrolled in the prospective population-based Mayo Clinic Study of Aging and underwent structural MRI, amyloid PET imaging, and tau PET imaging. A fully automated machine-learning algorithm that had been developed previously in house was used to detect neuroimaging features of HCTS. On the basis of PET and MRI measures, participants were classified as having normal (A−) or abnormal (A+) amyloid, normal (T−) or abnormal (T+) tau, and normal (N−) or abnormal (N+) neurodegeneration. The neuropsychological battery assessed domain-specific and global cognitive scores. Gait speed also was assessed. Analyses were adjusted for age and sex.ResultsOf 684 participants, 45 (6.6%) were classified with HCTS according to the automated algorithm. Patients with HCTS were older than patients without HCTS (mean [SD] 78.0 [8.3] vs 71.9 [10.8] years; p < 0.001). More were cognitively impaired after age and sex adjustment (27% vs 9%; p = 0.005). Amyloid PET status was similar with and without HCTS, but tau PET standard uptake value ratio (SUVR) was lower for those with HCTS after age and sex adjustment (p < 0.001). Despite a lower tau SUVR, patients with HCTS had lower Alzheimer disease (AD) signature cortical thickness. With the amyloid-tau-neurodegeneration framework, HCTS was overrepresented in the T−(N)+ group, regardless of amyloid status.ConclusionThe HCTS pattern represents a definable subgroup of non-AD pathophysiology (i.e., T−[N]+) that is associated with cognitive impairment. HCTS may confound clinical and biomarker interpretation in AD clinical trials.

ObjectiveTo compare [18F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ).MethodsThirty-one participants with svPPA underwent MRI and Pittsburgh compound B–PET scanning, and 17 of these also underwent [18F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [18F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(−) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(−) controls.ResultsOf the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(−) participants. svPPA showed elevated [18F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia.ConclusionAlthough [18F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [18F]AV-1451 in svPPA is related to binding paired helical filament tau.

ObjectiveTo describe the prevalence of cerebral microbleeds (CMBs) and determine the association between CMBs and β-amyloid burden on PET.MethodsFrom the population-based Mayo Clinic Study of Aging, 1,215 participants (53% male) underwent 3-tesla MRI scans with T2* gradient recalled echo sequences from October 2011 to February 2017. A total of 1,123 participants (92%) underwent 11C-Pittsburgh compound B (PiB)-PET scans. The prevalence of CMBs was derived by adjusting for nonparticipation and standardizing to the Olmsted County, MN, population. The relationship between β-amyloid burden and CMB presence and location was tested using logistic regression models. Ordinal logistic models tested the relationship between CMB frequency and β-amyloid burden.ResultsTwo hundred seventy-four participants (22.6%) had at least one CMB. CMB frequency increased with age by decade (11% aged 60–69 years, 22% 70–79 years, and 39% 80 years and older). After adjusting for age, sex, and hypertension, PiB standardized uptake value ratio (SUVR) was associated with increased odds of a CMB. The association between PiB SUVR and CMBs was location-specific; PiB SUVR was associated with lobar CMBs but not deep CMBs. Age, hypertension, and PiB SUVR were associated with increasing CMB count. CMB density was greatest in parietal and occipital regions; β-amyloid burden correlated with concentration of CMBs in all lobar regions. Among participants with multiple CMBs, greater PiB uptake occurred in the pre- and postcentral gyri superiorly, the superior parietal lobe and precuneus, the angular gyrus, inferior temporal gyrus, and temporal poles.ConclusionsThe prevalence of CMBs increases with age. In this population-based sample, β-amyloid load was associated with lobar but not with deep CMBs.

ObjectiveThe effects of 2 frequently used formulations of menopausal hormone therapy (mHT) on brain structure and cognition were investigated 3 years after the end of a randomized, placebo-controlled trial in recently menopausal women with good cardiovascular health.MethodsParticipants (aged 42–56 years; 5–36 months past menopause) were randomized to one of the following: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 μg/d transdermal 17β-estradiol (tE2); or placebo pills and patch for 4 years. Oral progesterone (200 mg/d) was given to mHT groups for 12 days each month. MRIs were performed at baseline, at the end of 4 years of mHT, and 3 years after the end of mHT (n = 75). A subset of participants also underwent Pittsburgh compound B–PET (n = 68).ResultsVentricular volumes increased more in the oCEE group compared to placebo during the 4 years of mHT, but the increase in ventricular volumes was not different from placebo 3 years after the discontinuation of mHT. Increase in white matter hyperintensity volume was similar in the oCEE and tE2 groups, but it was statistically significantly greater than placebo only in the oCEE group. The longitudinal decline in dorsolateral prefrontal cortex volumes was less in the tE2 group compared to placebo, which correlated with lower cortical Pittsburgh compound B uptake. Rates of global cognitive change in mHT groups were not different from placebo.ConclusionsThe effects of oCEE on global brain structure during mHT subside after oCEE discontinuation but white matter hyperintensities continue to increase. The relative preservation of dorsolateral prefrontal cortical volume in the tE2 group over 7 years indicates that mHT may have long-term effects on the brain.Classification of evidenceThis study provides Class III evidence that the rates of change in global brain volumes and cognitive function in recently menopausal women receiving mHT (tE2 or oCEE) were not significantly different from women receiving placebo, as measured 3 years after exposure to mHT.

Objective:To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population.Methods:Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A−), reduced cortical thickness (N+/N−), and A+N+, A+N−, A−N+, or A−N−. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population.Results:Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%–23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%–31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A−N−: 61.4%; A+N−: 9.7%; A−N+: 17.4%; and A+N+: 11.5%, and varied by sex and by APOE ε4 carrier status. In men, prevalence estimates were as follows: A−N−: 62.6%; A+N−: 7.3%; A−N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A−N−: 60.4%; A+N−: 11.7%; A−N+: 15.3%; and A+N+: 12.6%. In ε4 carriers, prevalence estimates were as follows: A−N−: 54.6%; A+N−: 16.6%; A−N+: 12.4%; and A+N+: 16.4%. In non-ε4 carriers, prevalence estimates were as follows: A−N−: 63.3%; A+N−: 6.9%; A−N+: 19.9%; and A+N+: 10.0%.Conclusions:These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.

Objective:To assess whether noninvasive proton magnetic resonance spectroscopy (1H-MRS) tissue metabolite measurements at baseline can predict an increase in the rate of β-amyloid (Aβ) accumulation on serial PET in clinically normal (CN) older adults.Methods:Consecutive participants aged 60 years and older (n = 594) from the Mayo Clinic Study of Aging who were CN at baseline and who underwent 1H-MRS from the posterior cingulate voxel and longitudinal 11C-Pittsburgh compound B (PiB)–PET were included. The rate of Aβ accumulation by serial cortical PiB standardized uptake value ratios was estimated as a function of baseline 1H-MRS metabolite ratios and time using mixed-effect models adjusted for age, sex, and APOE ε4. Effect of APOE ε4 on the relationship between baseline MRS and an increased rate of Aβ accumulation was also assessed.Results:Among all participants, a higher myo-inositol (mI)/creatine (p = 0.011) and a lower N-acetylaspartate/mI (p = 0.006) at baseline were associated with an increased Aβ accumulation over time after adjusting for age, sex, and APOE ε4. APOE ε4 did not modify the association of baseline 1H-MRS metabolite ratios and rate of Aβ accumulation. However, APOE ε4 carriers accumulated Aβ faster than noncarriers regardless of the baseline Aβ load (p = 0.001).Conclusion:Among CN older adults, early metabolic alterations on 1H-MRS and APOE ε4 status are independently associated with an increased rate of Aβ accumulation. Our findings could have important implications for early diagnosis and identification of individuals for secondary prevention trials, because an increased rate of Aβ accumulation in CN older adults may confer a higher risk for cognitive decline and mild cognitive impairment.

ObjectiveTo evaluate FDG-PET as an antemortem diagnostic tool for Alzheimer-related TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy.MethodsWe conducted a cross-sectional neuroimaging–histologic analysis of patients with antemortem FDG-PET and postmortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center and Study of Aging with Alzheimer spectrum pathology. TDP-43-positive status was assigned when TDP-43-immunoreactive inclusions were identified in the amygdala. Statistical parametric mapping (SPM) analyses compared TDP-43-positive (TDP-43[+]) with TDP-43-negative cases (TDP-43[−]), correcting for field strength, sex, Braak neurofibrillary tangle, and neuritic plaque stages. Cross-validated logistic regression analyses were used to determine whether regional FDG-PET values predict TDP-43 status. We also assessed the ratio of inferior temporal to medial temporal (IMT) metabolism as this was proposed as a biomarker of hippocampal sclerosis.ResultsOf 73 cases, 27 (37%) were TDP-43(+), of which 6 (8%) had hippocampal sclerosis. SPM analysis showed TDP-43(+) cases having greater hypometabolism of medial temporal, frontal superior medial, and frontal supraorbital (FSO) regions (punc < 0.001). Logistic regression analysis showed only FSO and IMT to be associated with TDP-43(+) status, identifying up to 81% of TDP-43(+) cases (p < 0.001). An IMT/FSO ratio was superior to the IMT in discriminating TDP-43(+) cases: 78% vs 48%, respectively.ConclusionsAlzheimer-related TDP-43 proteinopathy is associated with hypometabolism in the medial temporal and frontal regions. Combining FDG-PET measures from these regions may be useful for antemortem prediction of Alzheimer-related TDP-43 proteinopathy.Classification of evidenceThis study provides Class II evidence that hypometabolism in the medial temporal and frontal regions on FDG-PET is associated with Alzheimer-related TDP-43 proteinopathy.

Objectiveβ-Amyloid (Aβ) pathology is common in patients with probable dementia with Lewy bodies (DLB). However, the pathologic basis and the differential diagnostic performance of Aβ PET are not established in DLB. Our objective was to investigate the pathologic correlates of 11C-Pittsburgh compound B(PiB) uptake on PET in cases with antemortem diagnosis of probable DLB or Lewy body disease (LBD) at autopsy.MethodsAutopsied cases who underwent antemortem PiB-PET and were assigned a clinical diagnosis of probable DLB or LBD at autopsy were included (n = 39). The primary endpoint was pathologic diagnosis of LBD, Alzheimer disease (AD), or mixed (LBD and AD) pathology; the secondary endpoints included Thal Aβ phase and diffuse and neuritic Aβ plaques.ResultsLower global cortical PiB standardized uptake value ratio (SUVr) distinguished cases with LBD from cases with AD or mixed pathology with an accuracy of 93%. Greater global cortical PiB SUVr correlated with higher Thal Aβ phase (r = 0.75, p ≤ 0.001). Voxel–based analysis demonstrated that Aβ pathology relatively spared the occipital lobes in cases with mixed pathology and LBD compared to cases with AD without LBD, in whom the entire cerebral cortex was involved. Global cortical PiB SUVr was associated primarily with the abundance of diffuse Aβ plaques in cases with LBD in a multivariable regression model.ConclusionLower PiB uptake accurately distinguishes cases with LBD from cases with AD or mixed pathology, correlating with the Thal Aβ phase. The severity of diffuse Aβ pathology is the primary contributor to elevated PiB uptake in LBD.Classification of evidenceThis study provides Class III evidence that lower PiB uptake accurately distinguishes patients with LBD from those with AD or mixed pathology.

ObjectiveTo determine the incidence of cerebral microbleeds (CMBs) and the association of amyloid PET burden with incident CMBs.MethodsA total of 651 participants, age ≥50 years (55% male), underwent 3T MRI scans with ≥2 separate T2*-weighted gradient recalled echo sequences from October 2011 to August 2017. Eighty-seven percent underwent 11C Pittsburgh compound B (PiB) PET scans. Age-specific CMB incidence rates were calculated by using the piecewise exponential model. Using structural equation models (SEMs), we assessed the effect of amyloid load and baseline CMBs on future CMBs after considering the direct and indirect age, sex, vascular risk factors, and APOE effects.ResultsParticipants' mean age (SD) was 69.8 (10.0) years at baseline MRI, and 111 participants (17%) had ≥1 baseline CMB. The mean (SD) of the time interval between scans was 2.7 (1.0) years. The overall population incidence rate for CMBs was 3.6/100 person-years and increased with age: from 1.5/100 new CMBs at age 50 to 11.6/100 person-years at age 90. Using the piecewise exponential model regression, the incidence rates increased with age and the presence of baseline CMBs. The SEMs showed that (1) increasing age at MRI or carrying an APOE4 allele was associated with more amyloid at baseline, and higher amyloid, particularly occipital amyloid load, in turn increased the risk of a new lobar CMB; and (2) the presence of CMBs at baseline increased the risk of a lobar CMB and had a larger effect size than amyloid load.ConclusionsAge and APOE4 carrier status act through amyloid load to increase the risk of subsequent lobar CMBs, but the presence of baseline CMBs is the most important risk factor for future CMBs.

ObjectiveTo assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.MethodsTau- and amyloid-PET were performed in 579 CU participants aged 50–98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A−) and normal/abnormal regional tau-PET (T+/T−). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30–49.ResultsHigher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A− and A+.ConclusionsTau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.

ObjectiveTo evaluate 18F-AV-1451 tau PET binding among microtubule-associated protein tau (MAPT) mutation carriers.MethodsUsing a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42–67 years) with clinically normal (CN) participants (n = 241, age range 42–67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52–67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology.ResultsTau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls.ConclusionsTau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non–exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.

ObjectiveTo describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.MethodsEight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.ResultsAll participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR ConclusionsThe participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.