Rankin, Katherine P.

AbstractBackgroundThe LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features.MethodThe Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3.ResultThe 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to >0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p<0.05).ConclusionKey neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.

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.

AbstractObjectiveThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health‐related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self‐rated and informant‐rated HRQoL would correlate with each other.MethodsIndividuals were classified using the Clinical Dementia Rating (CDR®) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL‐proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated.ResultsThe cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = −0.20, P = .001), as were ZBI and DEMQOL (r = −0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001).ConclusionLower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

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.

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.