Kukull, Walter A.

AbstractIntroductionThe CDR Dementia Staging Instrument PLUS National Alzheimer’s Coordinating Center (CDR plus NACC FTLD) was developed by adding to the standard CDR two extra domains focused on the main features of frontotemporal lobar degeneration (FTLD): language and behavior/personality. We intended to perform the validation studies for the European‐Portuguese population.MethodsA total of 105 participants matched for age, education, and disease staging (35 bvFTD, 35 AD, and 35 controls) were included. A translated‐version of the CDR and the two added domains was administered by a neuropsychologist who was blinded to the diagnosis.ResultsThe bvFTD group had higher baseline CDR plus NACC FTLD scores compared to the AD and controls. Only the sum‐of‐boxes (SB) score, the behavior/personality, and language domains were able to distinguish between clinical groups. Logistic regression analyses showed that adding the behavior/personality domain with or without language significantly enhanced the discriminating ability.DiscussionResults show that the CDR plus NACC FTLD is a reliable tool in the diagnostic process of bvFTD patients and has an added value in distinguishing them from patients with AD.

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

AbstractBackgroundClinicopathologic studies reported that the NACC Uniform Dataset (UDS) 2.0 core measures do not adequately differentiate patients who ultimately died of Frontotemporal Lobar Degeneration (FTLD) from Alzheimer’s disease (AD). The FTLD Module (FTLD‐MOD) assesses core features of behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). Initial investigations suggest that the FTLD‐MOD improves discrimination between biomarker‐supported bvFTD and typical late‐onset AD, and that clinically diagnosed PPA participants performed worse than bvFTD on all FTLD‐MOD language tasks. However, the utility of these measures in the differential diagnosis of AD vs. major FTLD syndromes in young‐onset cases remains underexplored.MethodWe examined participants with age‐of‐onset < 65 years in the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium and the Longitudinal Early Onset AD Study (LEADS). 115 bvFTD, 53 semantic variant PPA (svPPA), 29 non‐fluent variant PPA (nfvPPA) and 124 early‐onset AD (eoAD) cases completed the UDS3 and FLTD‐MOD. Linear regression analyses measured group differences in FLTD‐MOD raw scores and UDS3 neuropsychological z‐scores after accounting for group differences in demographic variables and global severity ratings. Alpha was 0.05 with Bonferroni corrections.ResultsParticipants with eoAD demonstrated the most impaired scores on tasks of attention, working memory, and processing speed, including Digit Span Backward (z=‐1.87) and Trails A (z=‐3.82). They also demonstrated difficulty on FTLD‐MOD language tasks with a working memory requirement (sentence repetition raw=3.68/5) and, as expected, memory (story delayed recall z=‐2.4z). svPPA performed the worst on FTLD‐MOD and UDS3 tasks assessing semantic memory, especially naming (all p’s ≤ 0.03). nfvPPA performed worst on sentence reading, sentence repetition, and letter fluency (all p’s ≤ 0.02). Consistent with previous work, these measures differentiate between bvFTD and PPA variants. However, relative to eoAD, bvFTD was equivalent (Trails B: bvFTDz=‐3.8, eoADz=‐3.82; p=0.12) or outperformed (sentence repetition: bvFTD=4.22/5, eoAD=3.68/5; p<0.001) the eoAD group on all tasks.ConclusionsWe undertook this analysis to compare performance of the major young‐onset sporadic AD and FTLD clinical syndromes in the ALLFTD and LEADS studies. Results demonstrate relatively distinct cognitive profiles among eoAD, svPPA, and nfvPPA, but not in bvFTD. Future analyses will include FTLD‐MOD behavioral symptom questionnaires to assess their utility in differentiating bvFTD.

AbstractPatients with early‐onset Alzheimer's disease (EOAD) are commonly excluded from large‐scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial‐ready network. LEADS will follow 400 amyloid beta (Aβ)‐positive EOAD, 200 Aβ‐negative EOnonAD that meet National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age‐matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post‐mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Abstract Introduction The Frontotemporal Lobar Degeneration Module (FTLD‐MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD‐MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 185), non‐fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data. Results Among PPAs, the FTLD‐MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change. Discussion The FTLD‐MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.

AbstractBackgroundThe LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features.MethodThe Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3.ResultThe 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to >0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p<0.05).ConclusionKey neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.

AbstractBackgroundDigital pathology and machine learning (ML) workflows have paradigm shifting potential especially in the field of Alzheimer’s disease and related disorders. However, many institutions/centers may not have access to these technologies. To provide benchmark data, a survey was developed and distributed to National Institutes of Health’s Alzheimer’s Disease Centers (ADCs) in the United States.MethodSurvey questions covered topics such as: infrastructure (i.e. type of digital slide scanners used), funding sources (i.e. how the scanner was funded), and data management/storage (i.e. size of digital files). After development, review, and approval by the ADC digital pathology working group, the survey was distributed via email to 35 past and current ADC directors and/or ADC neuropathology core leaders. Participation in the survey was completely voluntary and answers did not contain any personal data.ResultThe survey generated over a 90% response rate, and the majority of those who completed the survey were neuropathology core leaders; 81% stated their ADC had access to a digital slide scanner, most common brand being Aperio/Leica. One third of respondents stated there was a fee for service to utilize the scanner. For digital pathology and/or ML resources, 40% of respondents stated none are supported in any way by their ADC. To cover the purchase and operation of the scanner, 50% stated they had institutional support. Many were unsure of the approximate average scanned file size of digital images (37%) and total amount of storage space that files occupied (50%). Many (75%) were aware of other departments at their institution working with digital pathology and/or ML, but a similar percentage was unaware of multi‐university or industry partnerships.ConclusionThese results demonstrate many ADCs have access to a digital slide scanner and had institutional support to cover the purchase. However, further investigation is needed to understand hurdles and barriers for implementing both digital pathology and ML workflows aiding in standardized methods across ADCs.

AbstractObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.