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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.

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p

BACKGROUND Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread. OBJECTIVE This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers. METHODS This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences). RESULTS Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis. CONCLUSION Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

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.

Introduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. / Methods: Mutation carriers and non‐carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. / Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non‐carriers. Carriers who learned their status mid‐study had slightly higher levels of depression and lower cognitive scores. / Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid‐study may confer short‐term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.

BACKGROUND Age of manifest Huntington's disease (HD) onset correlates with number of CAG repeats in the huntingtin gene. Little is known about onset with 36 to 39 repeats, the "reduced penetrance" (RP) range. OBJECTIVES We provide allele-specific estimates of HD penetrance (diagnostic confidence level of 4) for RP allele carriers. METHODS We analyzed 431 pre-manifest RP allele carriers from Enroll-HD, the largest prospective observational HD study. Cumulative penetrance (CP) was estimated from Kaplan-Meier curves. RESULTS No one with 36 repeats (n = 25) phenoconverted. CP for 38 repeats (n = 120) was 32% (95% confidence interval [CI] 0%-55%) and 51% (CI, 10%-73%) by ages 70 and 75, respectively, and 68% (CI, 46%-81%) and 81% (CI, 58%-92%) by ages 70 and 75 for 39 repeats (n = 253). CP was not estimable at those ages for 37 repeats (n = 33). CONCLUSIONS Differences by RP-range repeat length did not reach significance with a 3-year median follow-up duration among censored individuals. © 2021 International Parkinson and Movement Disorder Society.

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Author(s): Boeve, Bradley F; Boxer, Adam L; Rosen, Howard J; Forsberg, Leah K; Heuer, Hilary W; Brushaber, Danielle; Appleby, Brian; Biernacka, Joanna M; Bordelon, Yvette M; Botha, Hugo; Brannelly, Patrick; Dickerson, Brad C; Dickson, Dennis W; Kimiko, Domoto‐Reilly; Faber, Kelley; Fagan, Anne; Fields, Julie A; Fishman, Ann; Foroud, Tatiana M; Galasko, Doug R; Gavrilova, Ralitza H; Gendron, Tania F; Geschwind, Daniel H; Ghoshal, Nupur; Goldman, Jill; Graff‐Radford, Jonathan; Graff‐Radford, Neill R; Grant, Ian; Grossman, Murray; Hsiung, Ging‐Yuek Robin; Huang, Eric J; Huey, Edward; Irwin, David J; Jones, David T; Kantarci, Kejal; Karydas, Anna M; Kaufer, Daniel; Knopman, David S; Kramer, Joel H; Kremers, Walter K; Kornak, John; Kukull, Walter A; Lagone, Emma; Leger, Gabriel C; Litvan, Irene; Ljubenkov, Peter A; Lucente, Diane E; Mackenzie, Ian R; Manoochehri, Masood; Masdeu, Joseph C; McGinnis, Scott; Mendez, Mario F; Miller, Bruce L; Miyagawa, Toji; Nelson, Kevin M; Onyike, Chiadi U; Pantelyat, Alex; Pascual, Belen; Pearlman, Rodney; Petrucelli, Leonard; Rademakers, Rosa; Ramos, Eliana Marisa; Rankin, Katherine; Rascovsky, Katya; Rexach, Jessica E; Ritter, Aaron; Roberson, Erik D; Rojas, Julio C; Sabbagh, Marwan N; Salmon, David P; Savica, Rodolfo; Seeley, William W; Staffaroni, Adam M; Syrjanen, Jeremy; Tartaglia, Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur W; Weintraub, Sandra; Wheaton, Diana; Wong, Bonnie; Wszolek, Zbigniew

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.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

The availability and cost of next-generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next-generation sequencing panels compared to single-gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi-structured interviews were performed at 6 months post-results about their experience. Two-sample t tests were performed on data collected at each time point to identify significant between-group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within-group change over time was assessed by a mixed-effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.

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.

Advances in genetic technology have revealed new information about the genetics of Parkinson disease (PD) and related disorders. While numerous genes have been associated with PD, a limited number have been proven to be causal. Mutations in three autosomal dominant genes (SNCA, LRRK2, and VPS35) and seven recessive genes (Parkin, PINK1, DJ1, FBXO7, DNAJC6, ATP13A2, and PLA2G6) are definitively pathogenic. Despite all these findings, the great majority of PD cases are not due to monogenic etiology. Many genetic risk factors have been linked to PD, of which GBA is recognized as the most important. This chapter reviews the current information about the genetics of PD and related disorders, including emerging evidence on genotype–phenotype correlations and biological mechanisms of disease. This information will assist in prognosis and identify pathways for treatment. Yet, because of the complexity of genetic information, genetic counseling is strongly recommended before and after testing.

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.

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

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.

Objectives: The cognitive indicators of preclinical behavioral variant Frontotemporal Dementia (bvFTD) have not been identified. To investigate these indicators, we compared cross-sectional performance on a range of cognitive measures in 12 carriers of pathogenic MAPT mutations not meeting diagnostic criteria for bvFTD (i.e., preclinical) versus 32 demographically-matched familial non-carriers (n = 44). Studying preclinical carriers offers a rare glimpse into emergent disease, environmentally and genetically contextualized through comparison to familial controls. Methods: Evaluating personnel blinded to carrier status administered a standardized neuropsychological battery assessing attention, speed, executive function, language, memory, spatial ability, and social cognition. Results from mixed effect modeling were corrected for multiplicity of comparison by the false discovery rate method, and results were considered significant at p < .05. To control for potential interfamilial variation arising from enrollment of six families, family was treated as a random effect, while carrier status, age, gender, and education were treated as fixed effects. Results: Group differences were detected in 17 of 31 cognitive scores and spanned all domains except spatial ability. As hypothesized, carriers performed worse on specific measures of executive function, and social cognition, but also on measures of attention, speed, semantic processing, and memory storage and retrieval. Conclusions: Most notably, group differences arose on measures of memory storage, challenging long-standing ideas about the absence of amnestic features on neuropsychological testing in early bvFTD. Current findings provide important and clinically relevant information about specific measures that may be sensitive to early bvFTD, and advance understanding of neurocognitive changes that occur early in the disease. (JINS, 2019, 25, 184–194)

ObjectiveTo characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness.MethodsThe present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers’ lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported.ResultsNon-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder.ConclusionFindings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder.

Hereditary neurodegenerative diseases can present with a psychiatric prodrome that overlaps with psychiatric symptoms that are not primary to these diseases. When individuals present for predictive testing while experiencing such symptoms, clinicians including genetic counselors, must proceed with caution and evaluate each situation on a case-by-case basis. Legitimate reasons may exist for moving forward with testing. Additionally predicting the consequences of testing is unrealistic so that the clinicians must do their best to prepare patients for both positive and negative results. A multidisciplinary team following the Huntington disease protocol remains the gold standard care for predictive testing for such patients. We discuss 3 case histories that demonstrate the complex nature of genetic counseling and testing in the presence of psychiatric symptoms, whether emanating from the disease itself or the results of living in an affected family.

To present recent findings on the links between the C9orf72 expansion and psychiatric impairment. Repeat hexanucleotide expansions in the C9orf72 gene are a cause of familial frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and the mixed phenotype, FTD-ALS. Symptomatic expansion carriers display higher rates of psychotic and other psychiatric symptoms than non-carriers. Neuroanatomical associations of these symptoms have been found in cortical and subcortical areas. Family members of symptomatic carriers have higher rates of primary neuropsychiatric disorders than control populations, and the C9orf72 expansion may contribute to this association. However, the expansion does not appear to directly cause primary psychiatric disorders. While there is strong evidence associating the C9orf72 expansion with psychotic symptoms in carriers and psychiatric disorders in their kindreds, the link between these two phenomena, if any, remains unclear.

Predictive genetic counseling for neurodegenerative diseases commenced with Huntington's disease (HD). Because the psychological issues and outcomes have been best studied in HD, the HD genetic counseling and testing protocol is still accepted as the gold standard for genetic counseling for these diseases. Yet, advances in genomic technology have produced an abundance of new information about the genetics of diseases such as Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. The resulting expansion of genetic tests together with the availability of direct-to-consumer testing and clinical trials for treatment of these diseases present new ethical and practical issues requiring modifications to the protocol for HD counseling and new demands on both physicians and genetic counselors. This work reviews the history of genetic counseling for neurodegenerative diseases, its current practice, and the future direction of genetic counseling for these conditions.

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.

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

This issue includes the first articles in a series on clinical application of precision medicine that Annals is publishing in collaboration with Columbia University. The editorialists discuss the n...

Background With Alzheimer’s disease and other dementias affecting approximately 7 million people in the United States, comprehension of the multitude of issues facing individuals with dementia and their families and compassion for them are essential components of good healthcare. The service learning program, A Friend for Rachel, was developed in 2011 to train pre-medical students about dementia and give them sustained exposure to people with dementia to foster understanding and compassion and decrease stigma,. The purpose of this study was to evaluate the impact of the program on pre-medical students. Methods Since 2011, 101 students participated in A Friend for Rachel. They were required to write weekly reflections about their interactions with their friends living with dementia. Each study author read these reflections to identify major recurrent themes. The authors discussed the themes and came to consensus. The reflections were then reread to analyze for sub-themes. Results Analysis of students’ reflections exposed five major themes: learnings about dementia, learnings about caregiving, their own experienced emotions, impact on career choice and learnings about good medicine, and impact on life. The reflections demonstrated appreciation of the issues raised by dementia, empathy for individuals living with dementia and their families, and comfort with people with dementia. The reflections also demonstrated how the program had a positive impact on the personal lives of the students. Conclusions Through experiencing a sustained relationship with a person living with dementia, A Friend for Rachel allows pre-medical students to re-evaluate their beliefs about dementia and appreciate the need for compassionate care for people with dementia. A Friend for Rachel also provides students with the opportunity to examine their personal lives and goals.

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.

The advent of next generation sequencing has changed genetic diagnostics allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer’s disease and frontotemporal dementia. However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of Alzheimer’s disease and frontotemporal dementia and to suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarker testing, Alzheimer’s disease and frontotemporal dementia can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis, specific etiology of the disease, provide information for the family, and eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests, so they can make an informed decision about testing.