Citations

Objectives The objective of this case study is to raise awareness of potential 123I-FP-CIT SPECT interference by lisdexafetamine dimesylate, a prodrug of d-amphetamine. Methods A 69-year-old man with Rapid Eye Movement sleep behavior disorder and mild cognitive impairment had been treated with lisdexafetamine dimesylate for attention-deficit/hyperactivity disorder. The patient had annual or biennial 123I-FP-CIT SPECT evaluations after their baseline visit at 69 years old. Nigrostriatal dopamine transporter uptake was semiquantitatively evaluated with 123I-FP-CIT SPECT using DaTQUANT 2.0 software. Lisdexafetamine dimesylate was discontinued 3 months before the sixth-year visit (76 years old) by his primary care provider. Results The patient had 4 123I-FP-CIT SPECT scans with lisdexafetamine dimesylate and 2 scans after the discontinuation of lisdexafetamine dimesylate. The DaTQUANT z-scores of the putamen declined from −1.36 at the baseline visit to −3.02 at the fifth-year visit. After the discontinuation of lisdexafetamine dimesylate, DaTQUANT z-scores of the putamen increased to −0.63 at the sixth-year visit and remained in the normal range of −0.71 at the seventh-year visit. Conclusions This case suggests that lisdexafetamine dimesylate may have a strong interference with 123I-FP-CIT SPECT, decreasing the tracer binding to the dopamine transporter and presenting false positive results.

AbstractBackgroundBoth 11C‐Pittsburgh compound‐B (PiB) and 18F‐Flutemetamol (FMT) have off‐target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid‐β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid‐β evaluations.MethodA cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54‐84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB‐PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut‐off of 22.ResultPiB and FMT visual positivity agreed with quantitative positivity on PiB‐based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid‐β positive) and centiloid (amyloid‐β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups.ConclusionDisagreements between amyloid‐β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near‐threshold cortical uptake, especially with FMT.

AbstractMayo Clinic Alzheimer’s Disease Research Center (ADRC) has been operational since 1990 supported by the US National Institutes of Health. In addition, in the aging and Alzheimer’s disease (AD) spectrum research, Mayo Clinic has been active in since 1986 with the Mayo Alzheimer’s Disease Patient Registry that evolved to the Mayo Clinic Study of Aging (MCSA) to become a population‐based study of aging and cognitive impairment in 2004.The overall goal of Mayo Clinic ADRC is to provide a structured environment that supports innovative research and enable translation aimed at accelerating the development of effective treatment and prevention for AD and related dementias at all stages of the disease. Our comprehensive ADRC is located in Rochester, Minnesota (MCR), and Jacksonville, Florida (MCF), and shares its operations in all of the Cores between the two geographic sites. ADRC core activities include the Administrative Core, Clinical Core, Data Management and Statistics Core, Neuropathology Core, Neuroimaging Core, Biomarker Core, the Outreach and Education Core (ORE Core), and the Research Education Component. ADRC Cores also interact directly with the MCSA.The theme of the center during the current cycle is “Similarities and Differences Among Neurodegenerative Disorders”. Therefore, in addition to focusing on the recruitment of participants along the AD spectrum, we continue to focus on the recruitment of persons on the frontotemporal lobar degeneration (FTLD) and the Lewy body disorders (LBD) spectra, including the prodromal stages of the neurodegenerative dementias.This focus expands on previous accomplishments of the ADRC across the neurodegenerative disease spectra. The acquisition and development of new biomarkers for the neurodegenerative diseases is a major focus of the Center, and the recruitment of research participants in all three disorders enhance randomized controlled trial studies.The Mayo ADRC interacts with other ADRCs on various collaborative efforts and supports Developmental Projects that utilize ADRC resources with the goal of attracting early‐stage and established investigators into the AD research field.

AbstractBackgroundSeveral studies suggest that premenopausal bilateral oophorectomy (PBO) is associated with an increased risk of cognitive impairment and dementia; however, the underlying brain changes are not well understood. Animal studies suggest that long‐term ovarian hormone deprivation in rats is associated with reduced white matter integrity, but few studies have been conducted among women. We assessed the impact of age at PBO before age 50 years on white matter integrity in a community‐based cohort of older women.MethodParticipants included 1,011 women enrolled in the Mayo Clinic Study on Aging (MCSA; 22 with PBO<40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years and 907 referent women). MCSA is a population‐based study of aging in Olmsted County, MN. PBO was abstracted from the medical records. Regional DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) were investigated using the Johns Hopkins University Atlas. Linear regression was used to examine the association between PBO age group and z‐scores of either FA or MD after adjusting for age at imaging and APOE.ResultThere were no differences in age at study visit (median = 72 years), education, APOE E4 frequency, or vascular comorbidities between the 3 groups of women with a history of PBO or referent women. Women with PBO<40 years, compared to referent women, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Women with PBO<40 years also had lower inferior frontal white matter FA and higher posterior thalamic radiation MD. Women who underwent PBO between 40‐44 years or 45‐49 generally did not have significant changes in white matter integrity compared to referent women.ConclusionWomen who underwent premenopausal bilateral oophorectomy prior to the age of 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for the education of women at a low risk for ovarian cancer who are considering PBO for benign conditions.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

Abstract Background The ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. ALLFTD represents the merger and continuation of two prior studies: Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Methods ALLFTD recruits participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS or PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. 26 sites in North America enroll participants for clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants; participants are requested to return annually for follow‐up evaluation. All participants are genotyped for dementia‐associated mutations. Participants also enroll in the FTD Disorders Registry for follow‐up surveys. A subset of participants undergo remote assessment via the ALLFTD app. Visits conducted under ARTFL and LEFFTDS are included in the ALLFTD dataset. Results ALLFTD has been successful in developing methods to conduct remote or hybrid visits and in actively evaluating participants. Since ALLFTD began in January 2020, 1034 participants (736 new; 298 previously enrolled in ARTFL or LEFFTDS) have been evaluated in the longitudinal arm; an additional 119 participants have been participated in a shortened, biofluid‐focused visit. 349 have returned for follow‐up visits. Including prior participants, the ALLFTD dataset contains 3871 visits from 2343 individuals. 1277 people have sporadic syndromes; 1045 were enrolled as familial. Among s‐FTLD, bvFTD is the most common phenotype (32.8%) followed by PSP (15.9%). 61.4% of f‐FTLD participants were clinically normal at first visit; bvFTD is the most common syndrome in symptomatic f‐FTLD (40%). 477 are confirmed carriers of FTLD‐associated genetic mutations. MRIs were obtained for 2594 visits; 3492 visits have associated blood biospecimens banked; 978 visits have associated CSF samples. Conclusions The ALLFTD consortium is actively evaluating participants across North America to better characterize FTLD syndromes and support the planning and development of FTLD clinical trials. Longitudinal datasets including clinical, genetic, and imaging data are available by request.

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.

AbstractBackgroundPosterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show overlapping patterns of hypometabolism affecting posterior regions of the brain. Both syndromes show disruptions in functional connectivity, but it is unknown how patterns of disruption within and between networks compare between PCA and DLB.MethodThirty amyloid‐positive PCA, 27 amyloid‐positive DLB (DLB+), 24 amyloid‐negative DLB (DLB‐) patients and 30 cognitively normal amyloid‐negative (CN) individuals were recruited at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore nine networks: visual, sensorimotor, dorsal‐attention, cerebellar, frontoparietal, memory, language, salience, and default mode networks (DMN). Multivariate linear regression models corrected for multiple comparisons and adjusted for age and sex were fit to analyze within‐network connectivity (Fisher’s R‐to‐Z transformations). Between‐network connectivity was assessed with group level difference maps (two‐sample t‐test) corrected for false discovery rate at p<0.05.ResultMultivariate linear regression models showed reduced within‐network connectivity across all DMN components, sensorimotor, and dorsal‐attention networks, with trends for the visual network in PCA compared to CN. Both DLB‐ and DLB+ showed reduced within‐network connectivity for the cerebellar network, with DLB+ showing reduced connectivity in the posterior‐DMN, memory, and salience networks compared to CN. DLB‐ showed increased connectivity in dorsal‐attention and DMN, while DLB+ showing reduced connectivity in the memory network compared to PCA. Between‐network analysis showed an increase in cerebellar‐to‐sensorimotor connectivity in all three groups, with increase in cerebellar‐to‐dorsal‐attention connectivity in DLB‐ and PCA compared to CN. DLB‐ showed a decrease in posterior‐DMN‐to‐sensorimotor connectivity, while PCA showed reduced connectivity between all DMN components and dorsal‐attention‐to‐sensorimotor connectivity compared to CN. There was an increase in connectivity between all DMN components and a reduction in dorsal‐DMN‐to‐sensorimotor connectivity in both DLB‐ and DLB+ compared to PCA.ConclusionPCA was associated with connectivity disruptions across all DMN components, sensorimotor, dorsal‐attention and visual networks, while both DLB groups showed disruptions in cerebellar networks, with DLB+ showing further disruptions in posterior‐DMN, memory and salience networks. These findings suggest that both PCA and DLB have unique brain network disruptions, with amyloid status influencing connectivity in DLB.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

AbstractBackgroundWe have previously shown that 3D T1‐weighted and 3D T2‐FLAIR brain MRI can potentially be re‐identified using face recognition, but this has not been tested for other MRI sequences commonly used in imaging studies of aging and dementia. Here we compare match rates of automated face recognition to re‐identify 3D T1‐weighted, 3D T2‐FLAIR, 3D T2‐weighted, 2D Axial T2‐FLAIR, multi‐echo GRE (T2*), diffusion MRI, functional MRI, ASL, and T2* GRE images.MethodWe used a dataset of 182 Mayo Clinic participants each with MRI and face photographs. MRIs used Siemens and GE vendor‐product sequences similar to ADNI3 and ADNI4 protocols. We created face reconstructions (“basic”, with minimal preprocessing, and “advanced” that automatically filled missing face regions using a template) from each MRI sequence, and we trained a Microsoft Azure PersonGroup face recognition classifier to recognize these MRI‐based faces. We then queried the classifier with five face photographs for each participant, and we recorded how often the classifier chose the correct MRI as the top‐ranked match. For image types with match rates > = 10%, we then repeated the experiment after de‐facing each MRI with mri_reface, our leading software that replaces faces in each image (“re‐faces”) with an average face.ResultResults are presented in Table 1. 3D T2‐FLAIR, 3D T1‐weighted, and 3D T2‐weighted images were matched at 96‐98%, and mri_reface reduced all to 8%. Axial T2‐FLAIR and ME‐GRE were matched at 32‐45%, and mri_reface reduced both to 1%. T2*‐GRE matched at 10%, and mri_reface reduced this to 1%. ASL matched at 8%, while dMRI and fMRI matched at only 0‐2%.ConclusionAmong current‐generation vendor‐product sequences, we recommend that de‐facing be applied before research data sharing of T1‐weighted, T2‐weighted, T2‐FLAIR, T2*, and ME‐GRE images. Minimal match rates for current‐generation product fMRI, ASL, and fMRI images suggest that they present low risk of re‐identification and can be shared without de‐facing, but this conclusion should be re‐evaluated if they are acquired without fat‐suppression, with a larger field of view, or if newer developments reduce the current levels of artifacts and distortion around the face.