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Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51).Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy.Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Author(s): Casaletto, KB; Staffaroni, AM; Wolf, A; Appleby, B; Brushaber, D; Coppola, G; Dickerson, B; Domoto-Reilly, K; Elahi, FM; Fields, J; Fong, JC; Forsberg, L; Ghoshal, N; Graff-Radford, N; Grossman, M; Heuer, HW; Hsiung, G-Y; Huey, ED; Irwin, D; Kantarci, K; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Litvan, I; Mackenzie, IR; Mendez, M; Miller, B; Rademakers, R; Ramos, EM; Rascovsky, K; Roberson, ED; Syrjanen, JA; Tartaglia, MC; Weintraub, S; Boeve, B; Boxer, AL; Rosen, H; Yaffe, K; ARTFL/LEFFTDS Study | Abstract: IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated g55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated gtwo-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Introduction Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

American Indians (AIs) generally consume less alcohol than the U.S. general population, although the prevalence of alcohol use disorder is higher. Binge drinking (the consumption of at least 5 standard alcohol units within a two-hour period) may confer heightened risk of cerebrovascular disease, resulting in vascular brain injury (VBI) or atrophy. We examined the contribution of binge drinking to risk of VBI and cerebral atrophy in older AIs. The Strong Heart Study and its ancillary study, Cerebrovascular Disease and Its Consequences in American Indians (CDCAI), comprises 25 years of longitudinal data collection on self-reported binge drinking behaviors; the CDCAI study also included brain MRIs. The sample size for this study was 817 participants. Binge drinking was independently associated with increased prevalence of abnormal sulcal or ventricle dilatation. These observed associations for cerebral atrophy are consistent with previous findings among children, among patients with alcohol use disorders and dependence, and among mental health patients. No known studies have reported these associations among general population adults. The mechanism for these effects may include neurotoxicity. The observed associations, especially those for hippocampal volume, are of unclear temporality. This is the first large cohort study to examine binge drinking as a risk factor for vascular brain injury and cerebral atrophy, independent of smoking, obesity, diabetes, hypertension, and hyperlipidemia, among older AIs.

Objectives:To examine factors that influence decision-making, preferences, and plans related to advance care planning (ACP) and end-of-life care among persons with dementia and their caregivers, and examine how these may differ by race.Design:Cross-sectional survey.Setting:13 geographically dispersed Alzheimer’s Disease Centers across the United States.Participants:431 racially diverse caregivers of persons with dementia.Measurements:Survey on “Care Planning for Individuals with Dementia.”Results:The respondents were knowledgeable about dementia and hospice care, indicated the person with dementia would want comfort care at the end stage of illness, and reported high levels of both legal ACP (e.g., living will; 87%) and informal ACP discussions (79%) for the person with dementia. However, notable racial differences were present. Relative to white persons with dementia, African American persons with dementia were reported to have a lower preference for comfort care (81% vs. 58%) and lower rates of completion of legal ACP (89% vs. 73%). Racial differences in ACP and care preferences were also reflected in geographic differences. Additionally, African American study partners had a lower level of knowledge about dementia and reported a greater influence of religious/spiritual beliefs on the desired types of medical treatments. Notably, all respondents indicated that more information about the stages of dementia and end-of-life health care options would be helpful.Conclusions:Educational programs may be useful in reducing racial differences in attitudes towards ACP. These programs could focus on the clinical course of dementia and issues related to end-of-life care, including the importance of ACP.

Author(s): Heuer, Hilary W; Wang, P; Rascovsky, K; Wolf, A; Appleby, B; Bove, J; Bordelon, Y; Brannelly, P; Brushaber, DE; Caso, C; Coppola, G; Dickerson, B; Dickinson, S; Domoto-Reilly, K; Faber, K; Ferrall, J; Fields, J; Fishman, A; Fong, J; Foroud, T; Forsberg, LK; Gearhart, D; Ghazanfari, B; Ghoshal, N; Goldman, J; Graff-Radford, J; Graff-Radford, N; Grant, I; Grossman, M; Haley, D; Hsiung, G-Y; Huey, E; Irwin, D; Jones, D; Kantarci, K; Karydas, A; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Kraft, R; Kremers, WK; Kukull, W; Litvan, I; Ljubenkov, P; Mackenzie, IR; Maldonado, M; Manoochehri, M; McGinnis, S; McKinley, E; Mendez, MF; Miller, BL; Onyike, C; Pantelyat, A; Pearlman, R; Petrucelli, L; Potter, M; Rademakers, R; Ramos, EM; Rankin, KP; Roberson, ED; Rogalski, E; Sengdy, P; Shaw, L; Syrjanen, J; Tartaglia, MC; Tatton, N; Taylor, J; Toga, A; Trojanowski, J; Weintraub, S; Wong, B; Wszolek, Z; Boeve, BF; Rosen, HJ; Boxer, AL; ARTFL and LEFFTDS consortia | Abstract: IntroductionBehavioral 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.

Author(s): Ramos, Eliana Marisa; Dokuru, Deepika Reddy; Van Berlo, Victoria; Wojta, Kevin; Wang, Qing; Huang, Alden Y; Deverasetty, Sandeep; Qin, Yue; van Blitterswijk, Marka; Jackson, Jazmyne; Appleby, Brian; Bordelon, Yvette; Brannelly, Patrick; Brushaber, Danielle E; Dickerson, Bradford; Dickinson, Susan; Domoto-Reilly, Kimiko; Faber, Kelley; Fields, Julie; Fong, Jamie; Foroud, Tatiana; Forsberg, Leah K; Gavrilova, Ralitza; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathan; Graff-Radford, Neill; Grant, Ian; Grossman, Murray; Heuer, Hilary W; Hsiung, Ging-Yuek R; Huey, Edward; Irwin, David; Kantarci, Kejal; Karydas, Anna; Kaufer, Daniel; Kerwin, Diana; Knopman, David; Kornak, John; Kramer, Joel H; Kremers, Walter; Kukull, Walter; Litvan, Irene; Ljubenkov, Peter; Lungu, Codrin; Mackenzie, Ian; Mendez, Mario F; Miller, Bruce L; Onyike, Chiadi; Pantelyat, Alexander; Pearlman, Rodney; Petrucelli, Len; Potter, Madeline; Rankin, Katherine P; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily; Shaw, Leslie; Syrjanen, Jeremy; Tartaglia, Maria Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur; Trojanowski, John Q; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew; Rademakers, Rosa; Boeve, Brad F; Rosen, Howard J; Boxer, Adam L; ARTFL/LEFFTDS consortium; Coppola, Giovanni | Abstract: IntroductionThe 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.

Author(s): Miyagawa, Toji; Brushaber, Danielle; Syrjanen, Jeremy; Kremers, Walter; Fields, Julie; Forsberg, Leah K; Heuer, Hilary W; Knopman, David; Kornak, John; Boxer, Adam; Rosen, Howard J; Boeve, Bradley F; Appleby, Brian; Bordelon, Yvette; Bove, Jessica; Brannelly, Patrick; Caso, Christina; Coppola, Giovanni; Dever, Reilly; Dheel, Christina; Dickerson, Bradford; Dickinson, Susan; Dominguez, Sophia; Domoto-Reilly, Kimiko; Faber, Kelley; Ferrell, Jessica; Fishman, Ann; Fong, Jamie; Foroud, Tatiana; Gavrilova, Ralitza; Gearhart, Debra; Ghazanfari, Behnaz; Ghoshal, Nupur; Goldman, Jill S; Graff-Radford, Jonathan; Graff-Radford, Neill; Grant, Ian; Grossman, Murray; Haley, Dana; Hsiung, Robin; Huey, Edward; Irwin, David; Jones, David; Jones, Lynne; Kantarci, Kejal; Karydas, Anna; Kaufer, Daniel; Kerwin, Diana; Kraft, Ruth; Kramer, Joel; Kukull, Walter; Litvan, Irene; Lucente, Diane; Lungu, Codrin; Mackenzie, Ian; Maldonado, Miranda; Manoochehri, Masood; McGinnis, Scott; McKinley, Emily; Mendez, Mario F; Miller, Bruce; Multani, Namita; Onyike, Chiadi; Padmanabhan, Jaya; Pantelyat, Alexander; Pearlman, Rodney; Petrucelli, Leonard; Potter, Madeline; Rademakers, Rosa; Ramos, Eliana M; Rankin, Kate; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily; Sengdy, Pheth; Shaw, Leslie; Tartaglia, Maria C; Tatton, Nadine; Taylor, Joanne; Toga, Arthur; Trojanowski, John Q; Wang, Ping; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew | Abstract: IntroductionWe 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.

Introduction The 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. Methods We 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. Results Asymptomatic 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. Discussion Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Introduction Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). Methods We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. Results The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. Discussion The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

Introduction Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. Methods We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. Results Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). Discussion Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.