Fields, Julie A.

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.

AbstractBackgroundParkinson’s disease and dementia with Lewy bodies are characterized by abnormal iron deposition in the substantia nigra, which can be measured with quantitative susceptibility mapping (QSM) on MRI. However, neuropathologic validation of the increased QSM in the substantia nigra associated with Lewy body disease (LBD) is lacking. We compared substantia nigra QSM on antemortem MRI between patients with and without Lewy‐related pathology which was confirmed by autopsy in all cases.MethodWe studied cases with antemortem QSM who underwent autopsy from the Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging (n=54). Immunohistochemistry was performed with rabbit NACP antibody against the amino acids 98‐115 of the α‐synuclein protein to detect Lewy‐related pathology. After neuropathologic evaluation, cases were classified as LBD‐present (n=13) if they had Lewy‐related pathology and LBD‐absent (n=42) if they did not have Lewy‐related pathology. Alzheimer’s disease co‐pathology was present in 9 of the LBD‐present cohort (70%). QSM was calculated for the whole substantia nigra and the two sub‐regions: pars compacta and pars reticulata. Non‐parametric Wilcoxon rank‐sum test was used to compare substantia nigra QSM values between LBD‐present and LBD‐absent cases. Area under the curve (AUC) analyses tested the accuracy of QSM to distinguish the two groups.ResultsLBD‐present group had higher QSM values in the substantia nigra than LBD‐absent group. Furthermore, sub‐regional analyses showed that the LBD‐present group had higher QSM in the substantia nigra pars compacta (p=0.008) but not in the pars reticulata than the LBD‐absent group (Figure 1). QSM of the substantia nigra pars compacta distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC=0.74; p=0.006; Figure 2).ConclusionThis study provides neuropathologic insight into the relevance of QSM of substantia nigra pars compacta as an in‐vivo biomarker of autopsy‐confirmed LBD. These findings indicate that imaging evidence of abnormal iron deposition in the substantia nigra may serve as a biomarker of Lewy‐related pathology in patients with primary LBD (i.e., Parkinson disease, dementia with Lewy bodies) and patients with potential LBD co‐pathology (e.g., patients with Alzheimer disease).

AbstractBackgroundDementia with Lewy bodies (DLB) frequently co‐occurs with Alzheimer’s disease (AD) pathologies, exacerbating disease progression. Biophysical models of diffusion imaging data, such as Neurite Orientation Dispersion and Density Imaging (NODDI), may reveal novel insights into the neurobiological substrates of AD on cortical and white matter microstructural injury.MethodA cohort of 57 DLB patients on the DLB spectrum (33 clinically probable DLB and 14 prodromal DLB) and 57 cognitively unimpaired (CU) controls underwent NODDI and PET imaging with [18F]‐Flortaucipir and [11C]‐PiB (Table 1). NODDI parameters were derived from white matter tracts and grey matter regions using the JHU “Eve” and Mayo Clinic Adult Lifespan Template atlases, respectively. Conditional logistic models were used to compare these parameters between the two groups, accounting for the 1:1 matching on age and sex. The associations of tau and amyloid‐β with NODDI parameters across the white matter tracts were examined with linear regressions. A region‐by‐region approach was adopted to evaluate the relationships of tau and amyloid‐β with grey matter NODDI, adjusting for age, APOE, and local grey matter volumes.ResultDLB spectrum patients exhibited extensive white matter abnormalities relative to CU, including lower fractional anisotropy, higher mean diffusivity (MD), and lower tissue‐weighted neurite density (tNDI). In grey matter, these deficits were paralleled with higher MD and lower tNDI and ODI, primarily in the temporoparietal and posterior cortices. Regression models revealed significant associations of elevated [18F]‐Flortaucipir uptake with deficits in temporal and limbic white matter tracts and a temporal‐lobe pattern of higher MD and lower tNDI in the cortex (Figure 1). No associations were observed with [11C]‐PiB in the DLB spectrum.ConclusionThese findings demonstrated an in vivo relationship between tau deposition and neurite deficits that spatially aligned with the canonical AD “cortical signature” of neurodegeneration in both white matter tracts and grey matter regions in DLB. Our study underscores the detrimental impact of AD pathology in DLB and provides a rationale for further investigations into the underlying mechanisms of AD in DLB. Future longitudinal studies tracking the progression of these changes could inform therapeutic strategies for DLB in the presence of AD pathologies

AbstractBackgroundAutopsy studies in Lewy Body Disease (LBD) indicate that cardiac sympathetic denervation precedes Lewy body pathology and neuronal loss in the brain. Myocardial 123I‐metaiodobenzylguanidine (MIBG) scintigraphy noninvasively assesses postganglionic cardiac sympathetic denervation in LBD and is considered an important biomarker in the international diagnostic criteria of Dementia with Lewy Bodies and Parkinson’s Disease (PD). Despite the internationally recognized importance of MIBG scintigraphy in LBD, its use in neurodegenerative disorders is not FDA approved for this indication and is rarely used in the US for neurological research. We sought to add MIBG scintigraphy to our multimodal imaging research in prodromal LBD. We launched pilot MIBG scintigraphy study in isolated REM Sleep Behavior Disorder (iRBD) individuals, who are typically regarded as representing evolving LBD.MethodWe conducted MIBG scintigraphy and 123I‐FP‐CIT SPECT in seven individuals with iRBD including two RBD with mild cognitive impairment (MCI), one with PD, and one healthy control (mean age of 71.5±8.3). Heart‐to‐mediastinum (H/M) ratio of the MIBG uptake on delayed image (3‐4 hours after Adreview® injection) was calculated with MIM. Cutoff value of 1.68 was used for determining abnormal H/M ratio (Yoshita et al, 2006). Nigrostriatal dopamine transporter uptake was evaluated with DaTQUANT 2.0 software.ResultFour iRBD participants including two RBD with MCI had abnormal MIBG scintigraphy (mean age 73.5±8.6, delayed H/M ratio 1.25±0.29)) and three iRBD participants had a normal scan (mean age 67.8±4.5, delayed H/M ratio 2.57±0.25). Delayed H/M ratio was 1.00 for the PD participant and 2.60 for healthy control participant. Among the four iRBD participants with abnormal MIBG scintigraphy, one participant had 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score <‐2.0 and three participants had z‐score in the range of ‐1.5 and ‐1.0. All iRBD participants with normal MIBG scintigraphy had normal 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score >‐1.0.ConclusionMIBG scintigraphy was abnormal in half of this small cohort. Our preliminary data suggests its utility in detecting early signs of evolving LBD. Increasing the number of the MIBG scintigraphy in iRBD participants and controls are planned to determine if MIBG scintigraphy can facilitate early detection of progression for use in clinical trials targeting LBD.

Abstract Background The Mayo Clinic Study of Aging (MCSA) is a longitudinal, population‐based study of residents of Olmsted County, Minnesota, USA. MCSA is releasing de‐identified clinical and imaging data on GAAIN.org to benefit the research community. Method We included longitudinal clinical data from all participants of the Mayo Clinic Study of Aging 30‐90 years of age (average 70.0y) through the first 15 years of the study. Clinical data includes age, sex, self‐reported race/ethnicity, APoE4 allele status, cognitive impairment status (normal, MCI, dementia, or other), height, weight, blood pressure, multi‐domain neuropsychological scores, neuroimaging summary measurements, medications, cardiovascular risk factors, social activity, sleep, mood/anxiety, functional measures, and more. For our initial release of imaging data, we selected the first imaging timepoint acquired on 3T GE MRI scanners and amyloid (PiB) PET during the same visit, from all available imaging participants 50‐90 years of age (average 70.7y). Currently, we included 3D T1‐weighted (MPRAGE) MRI (1x1x1.2mm 3 ), T2‐weighted FLAIR MRI (0.85x0.85x3.6mm 3 ), diffusion MRI (2.7mm resolution with 41 directions at b=1000 and 5 b=0), and numeric cortical global SUVR and Centiloid values from PiB PET scans at 40‐60 minutes post‐injection. All images are released in DICOM format and thoroughly de‐identified using CTP while ensuring preservation of necessary fields for analyses. T1‐weighted and T2‐FLAIR MRI were also de‐faced (identifiable face imagery was removed and replaced with an average) using mri_reface version 0.3.3 to further protect participants’ privacy, and all de‐faced images were visually inspected by a trained data scientist for quality assurance. Result The first phase of our public data release includes clinical data from 5925 unique participants from the Mayo Clinic Study of Aging (MCSA), each ranging from 1‐12 visits at roughly 15‐month intervals, and three MRI sequences (T1‐w, T2‐w‐FLAIR, and diffusion) from 1802 unique participants. Demographic summaries are given in Table 1. Conclusion This large, richly characterized, de‐identified clinical and imaging dataset is available to the research community at https://www.gaaindata.org/partner/MCSA , and it is suitable for a wide range of research uses. Additional data will be released over time, including de‐faced amyloid PET images.

AbstractBackgroundThe Mayo Clinic Study of Aging (MCSA) is a longitudinal, population‐based study of residents of Olmsted County, Minnesota, USA. MCSA is releasing de‐identified clinical and imaging data on GAAIN.org to benefit the research community.MethodWe included longitudinal clinical data from all participants of the Mayo Clinic Study of Aging 30‐90 years of age (average 70.0y) through the first 15 years of the study. Clinical data includes age, sex, self‐reported race/ethnicity, APoE4 allele status, cognitive impairment status (normal, MCI, dementia, or other), height, weight, blood pressure, multi‐domain neuropsychological scores, neuroimaging summary measurements, medications, cardiovascular risk factors, social activity, sleep, mood/anxiety, functional measures, and more. For our initial release of imaging data, we selected the first imaging timepoint acquired on 3T GE MRI scanners and amyloid (PiB) PET during the same visit, from all available imaging participants 50‐90 years of age (average 70.7y). Currently, we included 3D T1‐weighted (MPRAGE) MRI (1x1x1.2mm3), T2‐weighted FLAIR MRI (0.85x0.85x3.6mm3), diffusion MRI (2.7mm resolution with 41 directions at b=1000 and 5 b=0), and numeric cortical global SUVR and Centiloid values from PiB PET scans at 40‐60 minutes post‐injection. All images are released in DICOM format and thoroughly de‐identified using CTP while ensuring preservation of necessary fields for analyses. T1‐weighted and T2‐FLAIR MRI were also de‐faced (identifiable face imagery was removed and replaced with an average) using mri_reface version 0.3.3 to further protect participants’ privacy, and all de‐faced images were visually inspected by a trained data scientist for quality assurance.ResultThe first phase of our public data release includes clinical data from 5925 unique participants from the Mayo Clinic Study of Aging (MCSA), each ranging from 1‐12 visits at roughly 15‐month intervals, and three MRI sequences (T1‐w, T2‐w‐FLAIR, and diffusion) from 1802 unique participants. Demographic summaries are given in Table 1.ConclusionThis large, richly characterized, de‐identified clinical and imaging dataset is available to the research community at https://www.gaaindata.org/partner/MCSA, and it is suitable for a wide range of research uses. Additional data will be released over time, including de‐faced amyloid PET images.

AbstractBackgroundMany treatments targeting frontotemporal lobar degeneration (FTLD) are in the developmental pipeline, but the rarity of the disease, coupled with the behavioral and motor features of FTLD, make it challenging to identify sufficient trial participants who can attend frequent in‐person visits. Decentralized clinical trial designs with remote evaluations are attractive alternatives but require validated tools for symptom tracking. Our previous cross‐sectional analyses showed that cognitive tasks deployed via the ALLFTD Mobile App are reliable and sensitive to early stages of disease. The current study seeks to evaluate whether unsupervised smartphone cognitive tests are sensitive to longitudinal changes that occur with increasing FTLD disease stage.MethodThe study included 194 participants (mean baseline age 54.30, SD = 15.66; mean education = 16.52, SD = 2.31; 55.2% women) who were asymptomatic (Clinical Dementia Rating plus FTLD (CDR®+NACC‐FTLD) = 0 [n = 109; 43 carriers of FTLD‐associated genetic variants]), prodromal (CDR®+NACC‐FTLD = 0.5 [n = 39]), or symptomatic (CDR®+NACC‐FTLD>0.5 [n = 46]) at baseline. Participants completed ALLFTD Mobile App smartphone versions of Stroop, flanker, and 2‐back tasks, as well as an adaptive associative memory task, every six months for up to two years. Linear‐mixed effects models investigated the effect of disease severity on cognitive trajectories by testing the interaction of baseline CDR®+NACC‐FTLD box score and time on smartphone test scores. Analyses were repeated in the subsample of asymptomatic/prodromal CDR®+NACC‐FTLD<1) familial FTLD mutation carriers (C9orf72, n = 27; MAPT, n = 16). All models controlled for age, education, and sex.ResultGreater baseline disease severity was associated with lower cognitive scores across all tasks (β range: ‐0.28 to ‐0.13; p’s < 0.001), and faster rates of decline on the memory and 2‐back tasks (β range: ‐0.15 to ‐0.07; p’s<0.04). When the sample was restricted to asymptomatic and prodromal individuals (CDR®+NACC FTLD<1), greater baseline disease severity was still associated with lower scores across most tasks (β range: ‐0.48 to ‐0.27; p’s<0.002; 2‐back: β = ‐0.19, p = 0.26). When the sample was restricted to asymptomatic/prodromal mutation carriers, disease severity remained associated with the memory and flanker tasks (β range: ‐0.85 to ‐0.45; p’s<0.01).ConclusionThis study provides initial evidence that longitudinal smartphone‐based cognitive measurements capture the accelerated cognitive worsening that accompanies increasing disease progression in FTLD.

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neuropathologically‐defined disease, and it is frequently comorbid with Alzheimer’s disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE‐NC) is not defined. We propose a set of clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE‐NC. These criteria assess degree of certainty (highest, high, moderate, low) based on features that are measurable in vivo, including older age at evaluation, a mild clinical syndrome, impaired semantic knowledge, disproportionate hippocampal atrophy, limbic hypometabolism, absence of neocortical degeneration patterns and low likelihood of neocortical tau. We operationalized these criteria using two large datasets with clinical and pathologic outcomes.MethodWe screened autopsied patients from Mayo Clinic and ADNI cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). We compared frequencies of neuropathological diagnoses across LANS likelihoods, compared longitudinal CDR‐SB trajectories across LANS likelihoods, and stratified ADNC/LATE‐NC patients according to their LANS likelihood and compared their longitudinal CDR‐SB trajectories to those with ADNC or LATE‐NC.ResultADNC, ADNC/LATE‐NC and LATE‐NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively (Fig. 1). ADNC cases had the lowest LANS likelihoods, LATE‐NC patients had the highest likelihoods, and ADNC/LATE‐NC patients had intermediate likelihoods. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo‐limbic degeneration compared to those with low likelihoods (Fig. 2). ADNC/LATE‐NC patients with higher likelihoods had more temporo‐limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo‐parietal degeneration and a faster rate of cognitive decline (Fig. 3).ConclusionThe implementation of LANS criteria has implications for disambiguating the different driving etiologies of progressive amnestic presentations in older age to guide prognosis, treatment, and clinical trial design and enrollment. The development of in vivo biomarkers specific to TDP‐43 pathology are needed to further refine molecular associations between LANS and LATE‐NC and precise antemortem diagnoses of LATE.

Abstract Objective To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. Methods Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. Results The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001‐0.01] and DBP: β = 0.01 [95% CI, 0.003‐0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. Conclusion Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Abstract INTRODUCTION Premenopausal bilateral oophorectomy (PBO) before the age of 46 years is associated with an increased risk of dementia. We investigated the long‐term effects of PBO performed before age 50 years on amyloid beta (Aβ), tau, and neurodegeneration imaging biomarkers of Alzheimer's disease (AD). METHODS Mayo Clinic Cohort Study of Oophorectomy and Aging‐2 participants were divided into early PBO (< 46 years; n = 61), and late PBO (46–49 years; n = 51) groups and were compared to referent women who did not undergo PBO ( n = 119). RESULTS Early PBO was associated with thinner entorhinal cortex ( p = 0.014), higher tau load at higher levels of Aβ load ( Pp = 0.005), higher Aβ load ( p = 0.026), and smaller temporal lobe cortical thickness ( p = 0.022), only at older ages compared to the referent group. DISCUSSION PBO before the age of 46 years is associated with entorhinal cortex thinning, elevated tau at higher Aβ levels, along with an AD‐like pattern of atrophy at older ages. CLINICAL TRIALS REGISTRATION NCT03821857 sex‐specific effects of endocrine disruption on aging and AD. Highlights Premenopausal bilateral oophorectomy (PBO) before the ages of 46 (early PBO) years and ages 46 to 49 (late PBO) years was studied. Early PBO was associated with reduced entorhinal cortex thickness later in life. Early PBO was associated with greater amyloid beta (Aβ) load at older ages. Early PBO was associated with greater Alzheimer's disease pattern of atrophy at older ages. Early PBO was associated with higher tau load at higher Aβ levels.