Forsberg, Leah K.

AbstractIntroductionCaregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders.MethodsIn a sample of 558 participants with FTLD spectrum disorders, we performed multiple‐variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease.ResultsApathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician‐rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross‐sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia.DiscussionCaregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

AbstractIntroductionWe examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB).MethodsIn 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209).ResultsREM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles.DiscussionAn earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.

Abstract At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed ‘mild behavioural and/or cognitive impairment in bvFTD’ (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer’s disease, and the false positive rate of diagnosis was 11–16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

AbstractBackgroundImmune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.MethodsWe examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).ResultsPlasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.ConclusionPlasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.

AbstractBackgroundFamilial frontotemporal dementia (f‐FTLD) is typically caused by mutations in one of three genes: microtubule‐associated protein tau (MAPT), progranulin (GRN), and a repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Accurate characterization of the natural history of each mutation is important for clinical prognostication and clinical trial design, and it could shed light on disease biology. Such models have not been thoroughly developed using participants that represent all disease stages, with longitudinal data. We characterized the trajectory of atrophy in each gene by using longitudinal voxel‐wise analyses of gray matter volume, and we assessed whether functional independence declined in tandem.MethodF‐FTLD participants (n=100) with a known mutation (MAPT+ (n=28), GRN+ (n=33), C9orf72+ (n=39)) were grouped according to disease stage (CDR®+NACC FTLD module). We included participants with at least two structural MRIs at a given disease stage: presymptomatic (CDR®+NACC‐FTLD=0, n=57), mild/questionable (CDR®+NACC‐FTLD=0.5, n=15), and symptomatic (CDR®+NACC‐FTLD ≥1, n=28). We fitted longitudinal linear mixed effects models to extract mean atrophy rates in each lobe compared to longitudinal imaging from family members without mutations (n=60). All results presented below were significant at p<.001.ResultUsing the left frontal lobe as an exemplar, in the presymptomatic stage, MAPT mutation carriers showed the greatest rate of atrophy compared to controls (88 mm3/year more volume loss than controls), followed by GRN+ (65 mm3/year) and then C9orf72+ (49 mm3/year). In the mild/questionable stage, MAPT+ showed a greater divergence from controls (374 mm3/year) than did GRN+ (107 mm3/year) or C9orf72+ (223 mm3/year). In the symptomatic stage, MAPT+ again lost volume at the fastest rate (2,099 mm3/year), followed by GRN+ (1,360 mm3/year). C9orf72 expansion carriers showed a much slower rate of volume loss (115 mm3/year). Similar patterns were observed for other brain regions. In contrast to the imaging results, C9orf72+ exhibited similar rates of functional decline compared to GRN+ and MAPT+ at all levels of disease severity.ConclusionThe primary f‐FTLD genes show divergent atrophy trajectories as a function of disease stage, with C9orf72 expansion carriers exhibiting a slow degeneration throughout the disease course, possibly due to unique pathophysiological mechanisms.

AbstractBackgroundMultiple imaging modalities have been individually shown to be useful in diagnosing Dementia with Lewy Bodies (DLB). Reduced striatonigral uptake on ioflupane‐SPECT reflects striatonigral dopamine dysfunction observed in DLB, while other imaging modalities assess different aspects of DLB, which potentially work complementarily when used together. We assessed how well ioflupane‐SPECT differentiates DLB from Alzheimer’s Disease Dementia (ADem) and whether adding another imaging modality to ioflupane‐SPECT would provide additional value.MethodIoflupane‐SPECT, MRI, FDG‐PET, and PiB‐PET were assessed on 35 DLB and 14 ADem patients (including 12 patients with eventual autopsy confirmation). Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with ioflupane‐SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake. Hippocampal volume was calculated with structural MRI, cingulate island sign (CIS) ratio with FDG‐PET, and global cortical PiB retention with PiB‐PET.ResultLower DaTQUANT z‐scores of putamen were observed in DLB patients compared to ADem patients (c‐statistic 0.896, p<0.001). Ioflupane‐SPECT showed higher c‐statistic in differentiating DLB from ADem than hippocampal volume on MRI (c‐statistic 0.718, p=0.034), CIS on FDG‐PET (c‐statistic 0.869, p=0.003), or global cortical PiB retention on PiB‐PET (c‐statistic 0.869, p=0.002), but some overlap between two diagnostic groups was still observed with the single imaging modality. Among these imaging modalities, ioflupane‐SPECT was the only modality correlated with the Unified Parkinson Disease Rating Scale (UPDRS) part III, while only PiB‐PET correlated with Montreal Cognitive Assessment (MoCA) test score. Adding another imaging modality to ioflupane‐SPECT enhanced c‐statistics (+MRI c‐statistic 0.931, p<0.001; +FDG‐PET c‐statistic 0.957, p=0.005; +PiB‐PET c‐statistic 0.955, p=0.007), and ioflupane‐SPECT in combination with both FDG‐PET and PiB‐PET showed the highest c‐statistic of 0.974 (p=0.043).ConclusionIoflupane‐SPECT is an excellent imaging modality to identify DLB by detecting striatonigral dopamine dysfunction which is strongly associated with motor impairment in DLB. Correlative neuroimaging with MRI, FDG‐PET, or PiB‐PET may add small incremental value in differentiation of DLB and ADem. Supported by NIH grants (AG016574, AG006786, AG015866, NS100620, AG062677), grant from GE Healthcare, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Deal Family Foundation, and the Little Family Foundation.

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.

AbstractBackgroundCharacterization of the changes that occur throughout the transition from asymptomatic to symptomatic for those with familial frontotemporal dementia is essential for planning future disease‐modifying trials.MethodWe identified four related microtubule associated protein tau (MAPT) N279K mutation carriers who have phenoconverted from the asymptomatic to the symptomatic state. Key features were as follows: Case 1 (female) initial exam age 36, onset age 44, current age 49; Case 2 (male) initial exam age 39, onset age 43, current age 48; Case 3 (female) initial exam age 41, onset age 47, current age 53; Case 4 (male) initial exam age 36, onset age 37, current age 46. MRI and neuropsychological data were analyzed.ResultStructural MRI was analyzed using Tensor Based Morphometry Symmetric Diffeomorphic Image Normalization (TBM‐SyN) methodology to quantify lobar volumes, which was then analyzed using a Mixed Effects Model to determine the annual change in lobar volumes. The phenoconverters had a greater estimated annual rate of cortical atrophy in temporal (p <0.001), frontal (p <0.01) and parietal (p <0.05) lobes compared to non‐carriers, with the rate of annual change in symptomatic individuals double that of asymptomatic individuals. Annual change in the parietal and occipital lobes was also analyzed and found to be similar to healthy controls of a similar age. Raw scores on neuropsychological measures were converted to z‐scores for analysis. Category fluency, letter fluency, and Trails A and B were all impaired (z‐score <‐1.5) following phenoconversion, but performance on these and other measures was variable across these four in the late asymptomatic state.ConclusionFor each of the four phenoconverters, structural MRI changes preceded symptom onset, whereas neuropsychological performance was more variable and occurred in closer proximity to the time of phenoconversion. Decrements in verbal fluency and cognitive flexibility were observed earlier than other cognitive domains. These findings suggest that changes in frontal and temporal volume on MRI precede symptom onset, with regional brain volumes most consistently tracking the evolution from the asymptomatic to symptomatic state in N279K MAPT mutation carriers. Supported by: AG063911, AG045390, NS092089, AG016976, AG016574, AG062677.

AbstractBackgroundFrontotemporal dementia (FTD) can present with significant phenotypic heterogeneity. Most cases of sporadic FTD do not present for diagnosis until functional impairment is evident, making it difficult to identify and characterize the earliest features of FTD. Focusing on participants from families with known FTD‐causing pathogenic mutations allows for the characterization of the earliest features of FTD in genetic carriers.MethodThe ARTFL and LEFFTDS consortia (AG063911, AG045390, NS092089, AG016976) are joint, multi‐center cohort studies of patients with FTLD, including symptomatic and asymptomatic family members. For this study, a subset of ARTFL/LEFFTDS participants from families with known genetic mutations were selected if they were determined by a study physician to have (a) a phenotype of Mild Behavioral / Cognitive Impairment (MBI/MCI) and CDR®+NACC‐FTLD = 0.5 (44 participants, 19 C9orf72, 12 GRN, 13 MAPT mutations), or (b) CDR®+NACC‐FTLD = 1 (33 participants, 16 C9orf72, 10 GRN, 7 MAPT mutations). We examined the NACC Uniform Data Set (UDS) B9F form, bvFTD criteria. Pearson chi‐squared tests compared the frequency of identified bvFTD features between MBI/MCI and bvFTD participants.ResultThe most common bvFTD diagnostic criteria features questionably or definitely present in the 44 MBI/MCI participants were Apathy and Disinhibition, both at 30% (Within the early FTLD group: Apathy at 70% and Disinhibition at 72%). Neuropsychological testing deficits consistent with bvFTD were present in 27% (72%), and loss of empathy in 25% (72%). Impaired daily functioning was next at 16% (81%), Ritualistic behaviors were observed in 7%, (36%) and Hyperorality in 5% (33%). Chi‐squared tests revealed significant differences between the two groups for all features, with the largest numerical and statistical difference in impaired daily functioning.ConclusionApathy and Disinhibition were the most common neuropsychiatric symptoms noted in FLTD MBI/MCI. Development of impairments in daily functioning best distinguished the MBI/MCI and FTLD groups. This may be related to the requirement of functional impairment for the diagnosis of dementia. The relative frequency of different features in early dementia of genetic FTLD is similar to that reported in sporadic bvFTD. As more longitudinal data is collected, within‐subject assessment of the development of features in genetic bvFTD over time will be instructive.

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.