Bordelon, Yvette

AbstractBackgroundPlasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.MethodPlasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.ResultAt baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.ConclusionIn this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.

AbstractObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

AbstractIntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s‐bvFTD; mean age 63.3 years; 34% female) and 99 familial (f‐bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f‐bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule‐associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f‐bvFTD were younger and had earlier age at onset. s‐bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores due to more frequent endorsement of depression and irritability.Discussionf‐bvFTD and s‐bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

AbstractIntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

AbstractIntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia‐associated genes in 302 sporadic and 390 familial (symptomatic or at‐risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule‐associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

AbstractIntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2.DiscussionNonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

AbstractIntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial‐frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self‐monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.