Data stewardship in FTLD research: Investigator and research participant views.

INTRODUCTION: Federal policies and guidelines have expanded the return of individual results to participants and expectations for data sharing between investigators and through repositories. Here, we report investigators' and study participants' views and experiences with data stewardship practices within frontotemporal lobal degeneration (FTLD) research, which reveal unique ethical challenges. METHODS: Semi-structured interviews with (1) investigators conducting FTLD research that includes genetic data collection and/or analysis and (2) participants enrolled in a single site longitudinal FTLD study. RESULTS: Analysis of the interviews identified three meta themes: perspectives on data sharing, experiences with enrollment and participation, and data management and security as mechanisms for participant protections. DISCUSSION: This study identified a set of preliminary gaps and needs regarding data stewardship within FTLD research. The results offer initial insights on ethical challenges to data stewardship aimed at informing future guidelines and policies.

Living With Frontotemporal Degeneration: Diagnostic Journey, Symptom Experiences, and Disease Impact.

Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive declines in cognition, behavior, and personality. Hearing directly from individuals living with FTD and their care partners is critical in optimizing care, identifying meaningful clinical trial endpoints, and improving research recruitment and retention. The current paper presents a subset of data from the FTD Insights Survey, chronicling the diagnostic journey, symptoms, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease. Survey respondents included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses. Around half of survey respondents reported seeing three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick's disease. Participating independently in a range of activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the degree to which the lives of these individuals are affected even at the mild and moderate stages of disease. Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop therapies that improve quality of life.

Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort.

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 <.0001). CONCLUSION: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

INTRODUCTION: The 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. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among 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. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium.

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.

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

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.

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. METHODS: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. RESULTS: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. DISCUSSION: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

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.

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.

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.

The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology.

INTRODUCTION: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. METHODS: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. RESULTS: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. DISCUSSION: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

Nonlinear Z-score modeling for improved detection of cognitive abnormality.

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.

Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers.

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.

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.

The social and economic burden of frontotemporal degeneration.

OBJECTIVE: To quantify the socioeconomic burden of frontotemporal degeneration (FTD) compared to previously published data for Alzheimer disease (AD). METHODS: A 250-item internet survey was administered to primary caregivers of patients with behavioral-variant FTD (bvFTD), primary progressive aphasia, FTD with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. The survey included validated scales for disease staging, behavior, activities of daily living, caregiver burden, and health economics, as well as investigator-designed questions to capture patient and caregiver experience with FTD. RESULTS: The entire survey was completed by 674 of 956 respondents (70.5%). Direct costs (2016 US dollars) equaled $47,916 and indirect costs $71,737, for a total annual per-patient cost of $119,654, nearly 2 times higher than reported costs for AD. Patients ≥65 years of age, with later stages of disease, and with bvFTD correlated with higher direct costs, while patients <65 years of age and men were associated with higher indirect costs. An FTD diagnosis produced a mean decrease in household income from $75,000 to $99,000 12 months before diagnosis to $50,000 to $59,999 12 months after diagnosis, resulting from lost days of work and early departure from the workforce. CONCLUSIONS: The economic burden of FTD is substantial. Counting productivity-related costs, per-patient costs for FTD appear to be greater than per-patient costs reported for AD. There is a need for biomarkers for accurate and timely diagnosis, effective treatments, and services to reduce this socioeconomic burden.

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development.

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.