There is a growing recognition of the benefits of non-pharmacological interventions in individuals with dementia. However, limited studies have explored the impact of personally meaningful music in this population. This controlled pilot study aimed to determine if personally meaningful music is effective in improving mood and behavior, and if a person-centered approach to music-based interventions is feasible in individuals with dementia. Twenty individuals with dementia participated in a 6-week study in an Assisted Living community. A cohort of residents were exposed to a meaningful (MS) or control song with a wash-out period of 5 days between the two exposures. Each personal MS (e.g. wedding song, song from childhood) was identified by the participant or family member using a validated questionnaire. The control song was identified by interviewing nursing staff members. Participants were observed for 5 minutes before, during and after the exposure to music and emotions were recorded using the Observed Emotion Rating Scale (OERS). The Neurobehavioral Rating Scale (NRS) assessed behavior, and vital signs (BP and pulse) were collected before and after interventions. Average age of participants was 81 (SD= 8) years; 40% had Alzheimer's disease, 30% had Frontotemporal Dementia and 30% had Vascular Dementia. Adequate data for analysis were available for 18 participants (90%). OERS analysis demonstrated no group differences before music exposure; participants had more singing (p<0.001) and were less expressionless (p=0.002) during the MS condition (with a trend toward more pleasure), and had more singing (p=0.005) and were looking around more (p=0.034) after the MS. NRS analysis yielded minimal symptoms both pre- and post-intervention. Systolic BP was greater in the control song condition pre-intervention (p=0.007). This study demonstrates that personally meaningful music is a feasible intervention in individuals with dementia, and may have a direct impact on mood and behavior when compared to staff-selected non-meaningful music. The study also supports a person-centered, tailored approach to music-based intervention. Further studies need to assess the impact of personally meaningful music on objective biomarker indicators in different forms of dementia, and on long-term quality of life outcomes.
MAPT mutations typically cause behavioral variant frontotemporal dementia (bvFTD) with or without parkinsonism. Previous studies have shown that symptomatic MAPT carriers show atrophy in frontotemporal cortex, with mesial temporal lobes predominantly affected (Rohrer et al., 2010; Whitwell et al., 2009). For presymptomatic MAPT carriers, studies have been mixed, with studies showing either no apparent gray matter deficits, or deficits in region of interest parcellations (Dopper et al., 2014; Rohrer et al., 2015). We studied a large cohort of presymptomatic and symptomatic MAPT carriers using a voxelwise approach to further refine neuroanatomical deficits and to examine relationships between gray matter and age. We studied 16 symptomatic MAPT carriers (age 55.3 ± 9.0, 10 female), 45 presymptomatic MAPT carriers (age 39.7 ± 10.5, 24 female), and 109 healthy controls (age 48.8 ± 13.3, 56 female) who had structural brain MRI scans. Symptomatic MAPT carriers included 15 with behavioral variant frontotemporal dementia (bvFTD), among which two had comorbid progressive supranuclear palsy syndrome, and one had Parkinson's disease. One carrier had an amnestic Alzheimer's-like syndrome. Voxel-based morphometry was performed on T1 images using SPM12. We created smoothed gray matter probability maps to generate voxelwise gray matter w-maps, a method of quantifying the difference between an individual carrier's expected and actual gray matter values, to further examine structural deficits (Ossenkoppele et al., 2015). Symptomatic MAPT carriers had bilateral gray matter atrophy in frontal cortex, insula, striatum with mesial temporal atrophy present in all subjects. Presymptomatic MAPT carriers showed an anatomically similar yet milder pattern of gray matter deficits, focused within bilateral hippocampus, amygdala and lateral temporal cortices. Within these regions, deficits emerged in a subset of presymptomatic MAPT carriers as early as their late thirties, while the remaining presymptomatic carriers showed normal gray matter volumes throughout the entire age span studied. Our findings suggest that early mesial temporal gray matter deficits are detectable in a subset of presymptomatic MAPT carriers, and that these same regions were atrophied in all symptomatic MAPT carriers studied. Longitudinal studies will elucidate whether these gray matter deficits represent early neurodegeneration, neurodevelopmental deficits, or both.
INTRODUCTION: Sex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants. DISCUSSION: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.
The Lewy Body Dementias (LBD), which include dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), represent the second most common dementia syndrome after Alzheimer's disease dementia. There are several challenges associated with LBD, which include the lack of approved medications for most clinical features, lack of evidence on management principles, and absence of infrastructure for LBD clinical trials. The Lewy Body Dementia Association (LBDA) oversaw the development of the Research Centers of Excellence (RCOE) program with the primary goals of 1) improving LBD clinical care and 2) developing a clinical trials-ready network and the associated infrastructure. A nation-wide request for applications and review process was performed in 2017, and the inaugural investigator meeting was held in December 2017. Twenty-four centers were selected, and over 40 individuals participated in the investigator meeting. A survey revealed that over 1700 new and over 4800 established LBD patients are evaluated each year across the RCOE centers. The following items were identified as key objectives relating to improving clinical care: 1) identify the optimal tools for clinical diagnosis, 2) define the standards of care for management throughout the course of the disorder, 3) promote continuing medical education to health care providers, and 4) operate and maintain LBD-specific resources, support groups and programs. The key objectives relating to developing clinical trial network infrastructure include: 1) review the landscape of clinical measures and biomarkers pertinent to LBD trial methodology, 2) determine the optimal core and supplemental battery of measures for clinical trials, and develop new measures when needed, 3) expand relationships with industry partners, and 4) determine core principles for LBD trials. Several working groups and committees were established to address these objectives. These objectives address many of the priorities for LBD which were developed at the NAPA Alzheimer's Disease and Related Dementias Summit in 2016 (Corriveau et al, Neurology 2017;89:2381-2391) – particularly the highest priority goal of initiating more clinical trials in LBD. The LBDA RCOE investigators will update the scientific community as these objectives are addressed. Supported by the LBDA.
Abstract Background It 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. Method As 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. Result As 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. Conclusion The 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.
Abstract To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy–Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy–Richardson, 52 with a progressive supranuclear palsy–cortical variant (progressive supranuclear palsy–frontal, progressive supranuclear palsy–speech/language, or progressive supranuclear palsy–corticobasal), and 17 with a progressive supranuclear palsy–subcortical variant (progressive supranuclear palsy–parkinsonism or progressive supranuclear palsy–progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a ‘subcortical’ subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a ‘cortical’ subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy–subcortical cases and 81% of progressive supranuclear palsy–Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy–cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the ‘subcortical’ subtype was associated with worse clinical severity scores compared to the ‘cortical subtype’ (progressive supranuclear palsy rating scale and Unified Parkinson’s Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.
Frontotemporal 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.The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.Advancing 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.29% 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%).Favorable 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.
The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) consortium aims to 1) characterize the North American population of FTLD patients in preparation for clinical trials and 2) characterize longitudinal changes in familial FTLD (fFTLD) over one year to develop new clinical trial outcome measures. Participants are either symptomatic with a sporadic FTLD spectrum disorder, including bvFTD, CBS, FTD-ALS, nfvPPA, PSP, or svPPA (Project 1) or are at risk for or symptomatic with fFTLD with a potentially autosomal dominant syndrome, regardless of whether there is a known underlying mutation (Project 2). ARTFL is closely linked to the LEFFTDS project, sharing a common infrastructure and assessments. Participants receive clinical neurological exams, neuropsychological testing, medical history, and blood draw for biomarker collection as well as surveys on lifestyle factors, autoimmune disease history, and attitudes towards clinical trial participation. Familial participants return for a follow-up visit in one year. Asymptomatic family members also undergo MRI. All ARTFL participants are genotyped for FTLD-associated mutations. We report here the characteristics of 566 (288 female (51%)) participants enrolled over 15 sites through December 2016. 280 individuals with sporadic FTLD have been enrolled in Project 1 (mean age 66 years [range 34–89]) with the most common diagnoses being bvFTD (26.5%), PSP (19.3%), and svPPA±bvFTD (15.1%). CDR-SB scores were higher in bvFTD and PSP than svPPA; MDS-UPDRS was highest in PSP >> bvFTD >> svPPA (normal). Project 2 has enrolled 84 symptomatic (mean age 57.9 years; mean CDR-SB: 5.68) and 201 asymptomatic (mean age 47.7; mean CDR-SB: 0.03) fFTLD. ARTFL is actively enrolling participants across North America to characterize sporadic and familial FTLD and prepare sites and investigators for FTLD clinical trials. Clinical, biomarker, genetic and imaging data from ARTFL and LEFFTDS will soon be available to investigators worldwide.
Two NIH-funded research consortia have been designed to identify clinical trial cohorts, investigate disease progression, and develop new clinical trial outcome measures in frontotemporal lobar degeneration (FTLD). The Advancement of Research and Treatment in FTLD (ARTFL) protocol involves 18 clinical centers that evaluate participants with sporadic and familial FTLD. The 8-site Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) protocol co-enrolls ARTFL participants from kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). An integrated infrastructure was created for the two consortia with common procedures. Participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD-ALS, CBS or PSP) or with strong family histories of FTLD undergo clinical and neuropsychological evaluations and blood draws for genetic and biomarker analyses; lumbar puncture for CSF collection is optional. Familial participants return for yearly follow-up visits (ARTFL: 1 follow-up visit; LEFFTDS 3 follow-up visits). All participants are genotyped for dementia-associated mutations. To date, 1244 participants enrolled in ARTFL and LEFFTDS have undergone baseline assessment: 616 (49.5%) female, 1140 (91.6%) Caucasian, mean age 56 (range 18-89) years, and mean education 16 (range 11-22) years. The most common diagnoses in the sporadic cohort are bvFTD (30%) and PSP (21%), followed by CBS (13%), svPPA (12%), nfvPPA (10%), and FTD-ALS (4%). Of 586 familial participants, 25% have a MAPT mutation in the kindred, 20% have a GRN mutation in the kindred, 34% have the C9orf72 expansion in the kindred, and 4 individuals have a double familial mutation in C9orf72 and GRN. 16% of familial participants lacked known mutations, and a small number had other FTD-associated mutations. Annual follow-up evaluations for participants in the LEFFTDS study have been completed in 278 (71%) for Visit 2, 162 (41%) for Visit 3, and 35 (9%) for Visit 4. Blood samples are currently available from 1023 individuals and MRIs from 612 participants. These integrated consortia are actively evaluating participants across North America to characterize FTLD and prepare sites and investigators for FTLD clinical trials. Clinical, genetic, and imaging data and biospecimens are available to investigators worldwide.
Abstract Background There is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [ 18 F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). Method 38 participants underwent amyloid and [ 18 F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [ 18 F]PI‐2620 was administered. [ 18 F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS. Result Patients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, r s < 0.44, p > 0.05 uncorrected). Conclusion [ 18 F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.
