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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.

BackgroundMeasuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).MethodsWe measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal (‘asymptomatic non-converters’) and those who became symptomatic (‘asymptomatic converters’) using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).ResultsWe studied 394 participants (non-carriers=143,C9orf72=117,GRN=62,MAPT=72). InMAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. InC9orf72,higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=−0.16 (−0.22, −0.10), p2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).ConclusionsSystemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

BACKGROUND Compared to other types of dementia, family caregivers of people with LBD report higher stress and more severe depressive symptoms. OBJECTIVE We performed a pilot evaluation of a digital intervention designed to help caregivers address challenges that they have experienced, with the end goal of reducing psychological distress in this population. METHODS We recruited 15 family caregivers to participate in the quasi-experimental single-arm mixed methods study entitled VOCALE-LBD. The study offers an 8-week online intervention that uses a web-based discussion platform and involves moderation, peer-to-peer support, didactic training, and problem-solving skill enactment. RESULTS Participants’ baseline characteristics were as follows: Mean age (SD)= 66(8); 93% female; 100% White; and 53% had at least a post-graduate degree. Throughout the intervention, participants engaged in weekly online discussions, generating a total of 434 posts (average 4 posts/week). Attrition was 20%. At the study exit, participants showed improvements in depression, burden, stress, and loneliness. When we calculated differences in the proportion of participants with clinically significant improvement versus worsening of 0.5 SD or more for each outcome, we observed net improvements of 50%, 33%, 25%, and 25% in depression, loneliness, burden, and stress, respectively. When we assessed the benefits of participation, 75% of the participants reported that participation helped them to improve their understanding of LBD ‘a great deal,’ vs. 25% selecting the ‘some’ response option. Similarly, in response to a question about confidence in dealing with difficult behaviors of the care recipient, 50% of the participants selected ‘a great deal’, 42% ‘some’, and 8% ‘not at all’ response options. Finally, in response to a question about improvement in one’s abilities to provide care to the care recipient, 33% of the participants selected ‘a great deal’, 58% ‘some’, and 8% ‘not at all’ response options. CONCLUSIONS The study generated promising feasibility and efficacy data for a low-cost, online intervention designed for caregivers of persons with LBD. As the study was not powered for significance, we observed nominal average and net improvements in important psychological outcomes. Moreover, many caregivers reported that study participation helped them better understand the disease, feel more confident in dealing with difficult behavior of the care recipient, and improved their ability to care for the care recipient. If validated in future studies, the intervention could be an accessible, on-demand resource for caregivers to engage in moderated remote discussions with peers at their own convenience in terms of location, time of day and frequency. As far as pragmatic considerations, the intervention could be used in conjunction with caregiver usual care and as a stand-alone module in circumstances, such as current and future pandemic emergencies, when professional interventions in general and subspecialty care in particular might not be readily available.

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.

Background and ObjectivesFamilial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.MethodsWe screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy–Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.ResultsWe identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.DiscussionWe present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.Trial Registration InformationNCT02365922, NCT02372773, and NCT04363684.

New behavioral solutions are needed to improve health in persons with co-occurring frailty and dementia. Using dementia-specific principles of human-centered design, we developed a mobile intervention that includes a patient-facing app and clinician interface to promote a Mediterranean-style eating plan in this population. Our design processes were as follows. We first solicited iterative input from experts in dementia, accessible design, and technology concerning language, cognitive load, and overall accessibility needs in persons with early dementia. Next, we recruited seven people with mild dementia and their partners for interviews, experience sampling, and usability studies. Our primary findings were: 1) participants have basic knowledge of healthy eating tenets and want to learn more; 2) participants are unaware of anything specific to improve in their diet; 3) participants value simple meals with few ingredients; 4) participants strongly rely on physical cookbooks. Based on the results, we developed a high-fidelity prototype of the patient-facing mobile app, divided into tasks: 1) First time onboarding; 2) Setting the first dietary goal; 3) Finding a recipe; 4) Filter/sort for recipes; 5) Food tracking tool; 6) Mastering a dietary goal and starting a new one; 7) Reviewing progress. The resultant product was iterated in usability studies and informed a final prototype for further testing. In parallel, a web-based clinician interface was developed through individual interviews, a survey of potential end-users (n=24), and two rounds of usability studies (n=3 in each round). The online clinician product features these interactive modules: dashboard, tracking manager, patient portal, and individual patient page

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.

Alzheimer’s disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

Objective Autosomal‐dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early‐onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild‐type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ 1–40 compared to controls, indicating abnormal γ‐secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age‐matched control brain. Interpretation These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p

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.

Objective Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. Methods We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. Results The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. Interpretation AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117–128

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: We 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. METHODS: The 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. RESULTS: The 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. DISCUSSION: The 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 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.

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation−, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation−). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation−, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] −1.90 to −0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI −0.30 to −0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator’s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

Introduction Conventional 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. Methods In 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). Results Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2. Discussion Nonlinearly 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.

Mutations in the MAPT gene coding for the tau protein are one of the most common causes of familial frontotemporal dementia (FTD). In a previously described family with the V337M mutation in MAPT, we now report an affected woman who died at age 92 with a >40 year duration of symptoms, more than three times the mean disease duration in her family (13.8 years). Neuropathology showed the typical findings of a diffuse tauopathy. Conversely, her 67-year-old son with the same mutation remains asymptomatic more than 15 years beyond the mean age of onset in the family (51.5 years). These two cases demonstrate the marked variability in onset and duration of familial FTD and underscore the difficulties of discussing these issues with patients and families. The presumed genetic and environmental factors influencing these parameters remain largely unknown. © 2016 Wiley Periodicals, Inc.

A speech-language pathologist (SLP) may be one of the initial clinical providers for a patient with primary progressive aphasia (PPA), a group of neurodegenerative diseases involving the selective, progressive deterioration of speech and/or language abilities. While the three primary subtypes of PPA have distinct profiles of language preservation and impairment, the process of identifying the subtype can be challenging for many reasons, including subtle initial symptoms which can be difficult to detect on standard testing batteries. Early and accurate subtyping is important for clinical and research applications, which we will discuss here. The SLP plays a critical role in the initial subtyping process, as well as in helping to confirm that the course and presentation are consistent with a root diagnosis of PPA, as opposed to normal aging or other etiologies. The involvement of the SLP over time then focuses on monitoring symptom severity and progression, which is a particularly relevant issue for this population. The SLP can apply this information to inform treatment planning and patient/family counseling, and to assess potential benefits from interventions including conventional and novel speech therapies, and pharmaceutical treatments as they become available.

Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome involving the gradual development of aphasia, slowly impairing the patient's ability to communicate. Pharmaceutical treatments do not currently exist and intervention often focuses on speech-language behavioral therapies, although further investigation is warranted to determine how best to harness functional benefits. Efforts to develop pharmaceutical and behavioral treatments have been hindered by a lack of standardized methods to monitor disease progression and treatment efficacy.Here we describe our current approach to monitoring progression of PPA, including the development and applications of a novel clinical instrument for this purpose, the Progressive Aphasia Severity Scale (PASS). We also outline some of the issues related to initial evaluation and longitudinal monitoring of PPA.In our clinical and research practice we perform initial and follow-up assessments of PPA patients using a multi-faceted approach. In addition to standardized assessment measures, we use the PASS to rate presence and severity of symptoms across distinct domains of speech, language, and functional and pragmatic aspects of communication. Ratings are made using the clinician's best judgment, integrating information from patient test performance in the office as well as a companion's description of routine daily functioning.Monitoring symptom characteristics and severity with the PASS can assist in developing behavioral therapies, planning treatment goals, and counseling patients and families on clinical status and prognosis. The PASS also has potential to advance the implementation of PPA clinical trials.PPA patients display heterogeneous language profiles that change over time given the progressive nature of the disease. The monitoring of symptom progression is therefore crucial to ensure that proposed treatments are appropriate at any given stage, including speech-language therapy and potentially pharmaceutical treatments once these become available. Because of the discrepancy that can exist between a patient's daily functioning and standardized test performance, we believe a comprehensive assessment and monitoring battery must include performance-based instruments, interviews with the patient and partner, questionnaires about functioning in daily life, and measures of clinician judgment. We hope that our clinician judgment-based rating scale described here will be a valuable addition to the PPA assessment and monitoring battery.

The mild cognitive impairment (MCI) stage of neurodegenerative diseases refers to an early clinical phase of the disease in which a change has been observed in an individual's cognition or behavior but the person is generally able to maintain independent functioning in daily activities with minimal aids or assistance. At an early stage of most neurodegenerative diseases, including the Frontotemporal Dementias, it can be very difficult to determine whether a person has symptoms of a progressive illness or is suffering from a condition less likely to progress, or even exhibiting symptoms consistent with normal aging. It is critical to identify individuals with MCI, since people with this clinical syndrome are at elevated risk of progressive cognitive decline. In the case of Primary Progressive Aphasia, a neurodegenerative disease in which speech and/or language abilities are gradually lost, a speech-language pathologist (SLP) may be one of the initial clinical providers in the MCI stage. The SLP is therefore critical in helping to determine whether a change in language abilities is a result of normal aging, a neurodegenerative process, or other etiologies.

SUMMARY Primary progressive aphasia (PPA) is a gradually progressive syndrome that robs patients of the ability to communicate. There are a variety of diagnostic challenges; international consensus has only recently been reached on the nomenclature for specific subtypes and there are a variety of underlying neurodegenerative pathologies. There are at present no established treatments, and efforts to develop treatments have been hampered by the lack of standardized methods to monitor progression of the illness. Although measures developed from work with stroke aphasia and with disorders such as Alzheimer’s disease have provided a valuable foundation for monitoring progression, PPA presents unique challenges to clinicians aiming to counsel patients and families on clinical status and prognosis, and to experts aiming to design clinical trials of potential interventions. Here we review some of the issues facing the field of PPA clinical research, summarize our current approach to monitoring progression of PPA and outline some ideas regarding goals for the development of better tools for this purpose.