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IntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD=0 [N=101]; prodromal: 0.5 [N=49]; symptomatic ≥1 [N=51]; not measured [N=13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research.HighlightsThe ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

Introduction Caregivers 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. Methods In 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. Results Apathy 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. Discussion Caregivers 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.

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): Forsberg, Leah K; Boeve, Bradley F; Boxer, Adam L; Rosen, Howard J; Kornak, John; Heuer, Hilary W; Fields, Julie A; Brushaber, Danielle; Machulda, Mary M; Sturm, Virginia; Staffaroni, Adam M; Ljubenkov, Peter A; Denver, Reilly; Ong, Elise; Appleby, Brian; Bordelon, Yvette M; Brannelly, Patrick; Coppola, Giovanni; Dickerson, Brad C; Dickinson, Susan; Kimiko, Domoto-Reilly; Faber, Kelley; Fong, Jamie; Foroud, Tatiana M; Gavrilova, Ralitza H; Gearhart, Debra; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathan; Graff-Radford, Neil R; Grossman, Murray; Robin Hsiung, Ging-Yuek; Huey, Edward D; Irwin, David; Jones, David T; Kantarci, Kejal; Karydas, Anna M; Kaufer, Daniel; Kerwin, Diana R; Knopman, David S; Kraft, Ruth A; Kramer, Joel H; Kremers, Walter K; Kukull, Walter A; Litvan, Irene; Lucente, Diane E; Lungu, Codrin; Mackenzie, Ian R; McGinnis, Scott M; Mendez, Mario F; Miller, Bruce L; Onyike, Chiadi U; Pantelyat, Alex; Pearlman, Rodney; Petrucelli, Leonard; Potter, Madeline; Rademakers, Rosa; Ramos, Eliana Marisa; Rankin, Katherine; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily J; Shaw, Leslie M; Sutherland, Marg; Syrjanen, Jeremy; Tartaglia, Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur W; Trojanowski, John Q; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew

Introduction Amyloid imaging is a tool that has recently become available to dementia specialists evaluating patients with possible Alzheimer's disease. Studies have assessed the impact of amyloid imaging on diagnostic and treatment decisions, but patient and family perspectives have received less attention. Methods To examine how amyloid imaging affects the diagnostic experience of patients and families, we interviewed members of 26 patient-caregiver dyads with whom a neurologist discussed the option of amyloid positron emission tomography. Results Most participants who chose to undergo amyloid imaging would choose to do so again. Regardless of the scan outcome, patients and caregivers commonly expressed relief on learning the scan results. Some participants expressed expectations that were beyond scan capabilities. Discussion Amyloid imaging may provide information that patients and their families find useful. Clinicians must set correct expectations and ensure that families understand the limitations of amyloid imaging.

Author(s): Boxer, Adam L; Rosen, Howard J; Boeve, Brad F; Heuer, Hilary; Grossman, Murray; Coppola, Giovanni; Dickerson, Bradford C; Bordelon, Yvette M; Dheel, Christina; Faber, Kelley; Fields, Julie A; Fong, Jamie; Foroud, Tatiana M; Ghoshal, Nupur; Graff‐Radford, Neil; Robin Hsiung, Ging‐Yuek; Huey, Edward D; Irwin, David J; Kantarci, Kejal; Kaufer, Daniel; Karydas, Anna; Knopman, David S; Kramer, Joel H; Kukull, Walter A; Litvan, Irene; Lungu, Codrin; Mackenzie, Ian R; Mendez, Mario F; Miller, Bruce L; Miller, Matt R; Onyike, Chiadi U; Pantelyat, Alex; Potter, Madeline; Rademakers, Rosa; Roberson, Erik D; Sutherland, Margaret; Tartaglia, Maria Carmela; Toga, Arthur W; Weintraub, Sandra; Wszolek, Zbigniew

Genetics studies have revealed a genetic contribution to susceptibility for common or sporadic forms of neurodegenerative disease such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supra-nuclear palsy (PSP, a syndrome characterized by oculomotor and gait abnormalities). In AD, early genetic mapping approaches have identified rare variants in genes such as APP, PSEN1, and PSEN2that cause familial, early-onset forms.1 APOE was also pinpointed as a late-onset AD susceptibility gene.2 Genome-wide association studies3–5 (GWAS) targeted toward common variants in primarily European populations have identified many variants associated with AD, most clearly near APOE but also consistently near ABCA7, BIN1, CLU, CR1, PICALM, SORL1, and other genes. Next-generation sequencing approaches have also found rare variants with strong effect in the MAPT and TREM2 genes.6,7 In FTD, the most frequently observed mutations in familial cases occur in C9ORF72, GRN, MAPT, TARDBP, and other genes.8 In sporadic cases, a haplotype variant on the long arm of chromosome 17 has been repeatedly associated with PSP.9–11 In addition, GWAS have been performed for sporadic cases of FTD, identifying associated single-nucleotide polymorphisms (SNPs) near TMEM106B12 and BTNL2/HLA-DRA/HLA-DRB5 and RAB38/CTSC,13 as well as for PSP, identifying associated SNPs near MAPT, EIF2AK3, STX6, and MOBP.11 Despite progress in understanding the genetics of neurodegenerative diseases, known genetic risk factors cannot explain a large portion of the heritability of these diseases. For example, in AD, all common variants (including known and unknown risk variants) have been predicted to account for less than 25% of disease variance,14 and known high-penetrance rare variants account for few cases, collectively totaling only a fraction of the estimated 58% to 79% heritability of AD.15 Some of this missing heritability may be due to a blind spot in conventional genetic studies to date. A moderately rare variant with moderate effect size would be too uncommon to be tagged by a standard genotyping array and have too small of an effect to be detected by linkage or genome sequencing in practical sample sizes. The exome array bridges this gap by genotyping at low cost more than 200 000 coding variants identified through sequencing studies (Figure 1). This approach has been applied to phenotypes such as insulin homeostasis,16 bronchopulmonary dysplasia,17 and heart disease.18,19 For AD, Chung et al20 recently reported an exome array study in Korean participants that found an association with APOE, APOC1, and TOMM40 variants (near the APOE locus) but did not identify novel genetic variants. Herein, we report findings from the application of the exome array to the multiancestral Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study cohort to determine the contribution of low-frequency coding variants to susceptibility to sporadic AD, PSP, and FTD. Figure 1 Comparison of the Exome Array and Related Genotyping and Sequencing Technologies

Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer's disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p =

Objective: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). Methods: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. Results: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy. Conclusions: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Summary Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. Methods We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. Findings Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI −3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, −0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Interpretation Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Funding Forest Research Institute.

Background/Aims: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. Methods: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. Results: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. Conclusion: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.