Forsberg, Leah K.

AbstractBackgroundFrontotemporal Dementia (FTD) patients are geographically dispersed and often have behavioral and/or motor deficits that limit access to in‐person clinical trials and research. To address these participation barriers, we investigated the feasibility of installing in‐home sensor technologies to remotely assess everyday functioning in FTD.MethodWe aimed to recruit 20 FTD participants with a variety of clinical syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). We also aimed to enroll a study partner for each participant that lived in the same home to serve as a control. The Collaborative Aging Research Using Technology (CART) platform was installed in participants’ homes to collect continuous data for up to two years, using motion sensors, physiological monitoring devices (e.g., scales, sleep sensors), electronic pillboxes, and wearable actigraphs. Computer use and driving patterns were also tracked. Technology was installed either via a study coordinator visit or remotely through video and written instructions, based on schedule and logistics. Participants were asked to complete a weekly Qualtrics survey about time away from home, visitors, and health changes.ResultOf the 159 UCSF participants available for recruitment through ALLFTD and other FTD projects, 28% (N = 45) met inclusion criteria. Of those 45, ten were ineligible due to advanced disease severity or relocation to an assisted living facility. A third (36%, N = 17) declined due to overwhelmed study partners (N = 3), declined any subproject participation (N = 7), sensitivity to participant’s diagnosis (N = 2), or lack of response (N = 5). Two additional participants were recruited through UCLA’s ALLFTD cohort. The platform has been installed in 19 homes (bvFTD: n = 10; PPA: n = 5; CBS/PSP: n = 4). Two homes discontinued due to death or relocation to assisted living facility. Mean data collection is 360 days (max = 527). Of 103 reported technological issues, 92% were resolved without additional home visits, either by phone or email. Participants completed 65% of weekly health questionnaires.ConclusionsAlthough there were some recruitment and retention challenges, these findings generally provide preliminary support for the feasibility and sustainability of conducting comprehensive in‐home passive data research in FTD.

AbstractBackgroundMemory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.MethodAssessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.ResultData from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).ConclusionThese data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.

AbstractBackgroundFrontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD.MethodParticipants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants’ smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age.Result57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 𝛃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 𝛃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 𝛃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 𝛃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day.ConclusionThese findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease.

AbstractBackgroundPathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers.MethodALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD.ResultFive treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect.ConclusionPlatform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure.

AbstractBackgroundGiven the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses.MethodsGenome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS.ResultsFirst, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm.ConclusionsThese lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies.

AbstractBackgroundThe ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f‐FTLD) to prepare for clinical trials in FTLD.MethodWe prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD‐CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI‐FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD‐CDR assessment. ANOVA was used to compare continuous variables, and chi‐square test was used to compare categorical variables across the groups.ResultThirty‐six participants (15 MAPT, 9 GRN, 12 C9orf72) developed MBCI during follow‐up visits, 13 participants (5 MAPT, 3 GRN, 5 C9orf72) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% (MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants (MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p<0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: “Memory” 36% (MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); “Orientation” 8% (MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); “Judgment/Problem Solving” 44% (MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); “Community Affairs” 22% (MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); “Home/Hobbies” 25% (MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); “Personal Care” 0%; “Behavior/Comportment/Personality” 44% (MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); “Language” 31% (MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12).ConclusionThe three most common FTLD‐CDR domains initially disturbed in the prodromal stage of fFTLD were “Behavior/Comportment/Personality”, “Judgment/Problem Solving”, and “Memory”, while “Orientation” was intact in the majority of the individuals. Memory impairment without disorientation was seen in one‐third of the prodromal fFTLD participants.

AbstractBackgroundThe DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit.MethodWe analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good).ResultDEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant’s overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC‐FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC‐FTLD = 0: 19.4%, CDR®+NACC‐FTLD = 0.5: 42%, and CDR®+NACC‐FTLD = 1+: 33.2%), worse than (CDR®+NACC‐FTLD = 0: 15.1%, CDR®+NACC‐FTLD = 0.5: 13.3%, and CDR®+NACC‐FTLD = 1+: 15.2%), or the same (CDR®+NACC‐FTLD = 0: 65.6%, CDR®+NACC‐FTLD = 0.5: 44.8%, and CDR®+NACC‐FTLD = 1+: 51.6%).ConclusionAmong participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC‐FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming.

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.

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

AbstractBackgroundWe aimed to assess axonal integrity in MAPT mutation carriers and early white matter (WM) neurodegeneration in asymptomatic carriers using traditional diffusion tensor imaging (DTI) measurements, i.e., fractional anisotropy (FA) and mean diffusivity (MD), and neurite orientation dispersion and density imaging (NODDI).MethodWe included available multi‐shell diffusion MRI data from 21 MAPT mutation carriers (16 asymptomatic; 5 symptomatic) and 31 non‐carrier family members as controls from the ALLFTD consortium. We used linear mixed‐effect models to assess WM abnormalities measured with FA and MD, neurite density index (NDI) and orientation dispersion index (ODI), combined across hemispheres. Separate models were conducted in all MAPT mutation carriers relative to controls while accounting for relatedness and age, then in symptomatic and asymptomatic carriers relative to controls. ComBat was used to harmonize data across sites.ResultIn models contrasting all MAPT carriers versus controls, WM alterations involved the cingulum bundle (FA, ODI), fronto‐temporal, entorhinal (FA, MD, NDI), and the inferior temporal WM (FA) after correcting for multiple comparisons (Fig. 1). In models contrasting symptomatic and asymptomatic MAPT carriers versus controls, symptomatic carriers had widespread involvement of the fronto‐temporal WM including the cingulum (FA, ODI), entorhinal (MD, FA, NDI), amygdala (MD, NDI) and inferior temporal (FA) areas after correcting for multiple comparisons. Asymptomatic carriers showed higher entorhinal MD and lower inferior temporal and cingulum FA relative to controls, and a more widespread pattern of higher ODI involved the medial temporal, superior temporal and occipital WM as well as long association and projection fibers including the internal capsule, cingulate bundle and fronto‐occipital fasciculi, although they were not statistically significant after correction for multiple comparisons.ConclusionTraditional DTI and novel NODDI measurements revealed some extent of overlap as well as divergences in patterns of WM abnormalities, indicating axonal loss is a feature of neurodegeneration in MAPT mutation carriers. Our results suggest that traditional DTI and novel NODDI measurements may have different sensitivities to WM alterations in MAPT mutation carriers, and that axon‐based metrics, particularly ODI measurements, may be more sensitive to the early WM involvement during the asymptomatic stage of the disease.