Boeve, Brad F

Abstract Background Corticobasal syndrome (CBS) is a neurodegenerative disease usually associated with accumulation of tau in the cortex and basal ganglia, leading to cognitive, movement, and behavioral symptoms that progressively impair function. Few clinical trials have ever been conducted in CBS, and perceptions and preferences about clinical trials in this population are largely unknown. Method An online survey was conducted (February 2015 ‐ November 2020) among research participants recruited through a multisite observational study (ARTFL). Responses from patients with CBS were tabulated and reported below. Result N=66 respondents had CBS as a primary or secondary phenotype (determined by study clinician), with 62% of surveys patient‐reported, and 38% completed by a caregiver/family member. Within CBS, 91% requested to be contacted about clinical trials. 2/6 decliners commented that disease severity precluded participation. 97% were willing to come in annually, 88% quarterly (3 months), 66% monthly, 43% weekly, and 17% would come in more than weekly; two patients could not travel due to disease severity. Comments included “we would live here for trials” and “whatever is needed.” Full day evaluations were acceptable to 91%, whereas 9% preferred a half‐day or less, although 65% would complete multi‐day evaluations spread over a week. Numerous remote and in person modes of assessment (e.g., surveys, examinations, cognitive testing, blood/saliva sampling, MRI, PET), were broadly acceptable by respondents (80‐93%), whereas remote activity monitoring (70%), lumbar puncture (68%), and remote video conferencing memory testing (67%) were less preferred, though still broadly acceptable. For distance willing to travel, 95% would travel 30 minutes, 91% one hour, 65% three hours, 54% five hours, and 37% would travel more than five hours or take a flight if needed. Travel reimbursement was very/extremely important for 40%, and unimportant for 26% (34% neutral). Feedback about clinical progression (81%), study results (74%), and an open‐label extension (68%) were factors identified as the highest importance to patients. Conclusion Patients with CBS are eager to participate in clinical trials, even trials that are complex, far away, and have visits over multiple days. Travel reimbursement, providing feedback to patients, and access to experimental treatments were key considerations.

Abstract Background Frontotemporal dementia (FTD) is a neurodegenerative disorder marked by early impairments in executive function and altered prefrontal neural circuitry. These traits are also observed in Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD), suggesting the possibility of shared mechanisms and a role for developmental neurocognitive factors in the onset of FTD. High‐penetrance mutations in GRN, C9orf72, and MAPT increase FTD risk and are suspected to influence neurodevelopment. This study hypothesizes that pre‐symptomatic carriers of these mutations exhibit cognitive and behavioral traits that overlap with those observed in ADD/ADHD. Method This cross‐sectional study analyzed participants from the ARTFL‐LEFFTDS Longitudinal FTLD (ALLFTD) Study. Inclusion criteria restricted the sample to mutation carriers with pathogenic variants in GRN, C9orf72, or MAPT while excluding individuals with prior psychiatric diagnoses (e.g., bipolar disorder, major depressive disorder) and those taking antipsychotic or anxiolytic medications to avoid potential confounding effects on test validity and interpretation. The final sample included N = 338 participants, categorized as pre‐symptomatic mutation carriers ( N = 227) or asymptomatic noncarriers ( N = 111). To assess potential overlaps with ADD/ADHD traits, a targeted subset of measures reflecting executive function, working memory, attention, social behavior, and hyperactivity were extracted from validated cognitive and neuropsychiatric assessments. Mutation carriers were further classified as either converters ( N = 20) who progressed to symptomatic FTD (CDR ≥ 1) or non‐converters ( N = 95) who remained asymptomatic. Only pre‐conversion scores were analyzed for converters. Group comparisons were conducted using general linear models adjusted for age and sex. Result Pre‐symptomatic mutation carriers showed significantly lower verbal fluency ( p = 0.004) and a trend toward reduced working memory ( p = 0.05) compared to noncarriers. Converters exhibited poorer overall cognitive performance ( p <0.0001), verbal fluency ( p = 0.001), and memory and attention ( p = 0.04) compared to non‐converters. Converters demonstrated higher Neuropsychiatric Inventory scores ( p = 0.0001), particularly in hyperactivity ( p = 0.003), reflecting greater behavioral disturbances. Conclusion Baseline impairments in cognitive function, memory, and neuropsychiatric profiles distinguish converters from non‐converters, highlighting overlaps between ADD/ADHD traits and prodromal FTD. These findings suggest shared neurobiological mechanisms and underscore the need for mutation‐specific studies to further explore the neurodevelopmental factors driving FTD progression.

Abstract Background Trials in Lewy body dementia (LBD) rely on scales and measurements created for Alzheimer’s disease and Parkinson’s disease. Industry and regulatory authority stakeholders and LBD triallists have recognised the absence of an LBD‐specific scale as critical unmet need in the drug development pipeline. Heterogeneity in LBD trials design, particularly concerning outcome measures, precludes effective evidence synthesis and data harmonisation. We describe the development of the Lewy Body Dementia‐Domain Rating Scale (LBD‐DRS) and a proposed roadmap for adoption and validation. Method Led by a core working group and steering committee, a three‐round Delphi survey process was used to establish consensus around the conceptual framework and preliminary content of the LBD‐DRS among invited LBD researchers and clinicians. “Consensus” was established when ≥75% of respondents concurred on any survey statement or questions. Result Consensus around the need for an LBD‐specific scale, specifically for use in early LBD, was established. After feedback was received for two early versions of LBD, a third version of LBD‐DRS has been further developed. This third version, and the results of the second Delphi survey round will be presented. A pragmatic approach, favouring an inclusive scoring approach for symptoms has been adopted, recognising that further iterations will be required once field data becomes available. Conclusion After consensus on the conceptual framework and preliminary content is established, the authors will consult with a broader range of stakeholders, including people living with LBD and their care partners, will be required to further develop LBD‐DRS. Engagement with regulatory bodies and the pharmaceutical industry will guide further development before validation studies are pursued.

Abstract Background Dementia with Lewy bodies (DLB) is a prevalent form of dementia associated with neuronal alpha‐synuclein aggregates (Lewy bodies). Symptoms include cognitive impairment, fluctuations, neuropsychiatric features including psychosis, sleep disorders, and dysautonomia. DLB is the most expensive form of dementia, and there are currently no treatments approved by the US FDA. Given the advent of sensitive and specific in vivo biomarkers for synuclein aggregation, drug developers are increasingly interested in DLB. FDA instituted Patient‐Focused Drug Development (PFDD) meetings in 2012 with the purpose of ensuring that patients’ experiences, perspectives, needs, and preferences are captured and meaningfully incorporated into drug development and evaluation. Method In October 2024, the Lewy Body Dementia Association (LBDA) and the Alzheimer’s Association (ALZ) co‐hosted an externally‐led PFDD (EL‐PFDD) meeting on DLB. Thirty days before the event, LBDA solicited public comment on the lived experience of DLB, the current state of treatment, and what people with DLB value in potential future therapies. During the live meeting, people with DLB, care partners and family members described their experiences and responded to live polling questions. Result The EL‐PFDD was attended by 347 people with DLB and care partners, drug developers (both industry and academic), FDA staff, and NIH staff. Preliminary analysis of the discussion content and survey responses shows several themes emerging from the meeting. The most bothersome and impactful symptoms varied over the course of the disease, but included cognitive impairment and fluctuations, neuropsychiatric symptoms, and sleepiness. Concerns for the future included progressive decline in cognition, changes in behavior/mood, and cost of care. Limitations to current treatments included lack of FDA‐approved medications, and side effects and lack of efficacy associated with “off label” medications. Priorities for future treatments included symptomatic treatments that do not worsen other DLB symptoms, slowing disease progression, accessibility/insurance coverage, and avoiding side effects. Conclusion The EL‐PFDD on DLB provided valuable information for drug developers and regulators to understand the lived experience of people with DLB and care partners. The results will be documented in a “Voice of the Patient” report that will be hosted at www.lbda.org/el‐pfdd .

Abstract Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Abstract Background Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS). Method We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. Result Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA ( p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. Conclusion This study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes.

Abstract Background Motor disturbances are common in neurodegenerative disorders. Digital health technologies can be a tool for remote, accessible, and low‐burden motor assessments. The ALLFTD Mobile App includes a finger‐tapping test (mApp‐FTT) to assess dexterity. We evaluated the reliability and construct validity of smartphone‐based measures of finger tapping in an in‐person sample. Methods Participants ( n = 33; mean age=68.2 [SD=8.6]) completed the mobile finger‐tapping test (mApp‐FTT) on iOS and Android devices (two counterbalanced 20‐second trials per hand) and the mechanical finger‐tapping test (FTT). The sample included cognitively unimpaired participants (22.2%) and those diagnosed with frontotemporal dementia‐spectrum disorders (41.7%), Alzheimer's dementia (22.2%), and progressive supranuclear palsy or corticobasal syndrome (13.9%). A motor domain was calculated based on neurological exam and added to the Clinical Dementia Rating® plus National Alzheimer's Coordinating Center–Frontotemporal Lobar Degeneration (CDR®+NACC‐FTLD). Pearson's correlations assessed associations between mApp‐FTT performance and FTT performance, clinical severity (CDR®+NACC‐FTLD Box Score), motor rating scales (Progressive Supranuclear Palsy Rating Scale [PSPRS] and Unified Parkinson's Disease Rating Scale [UPDRS]), and cognitive function. Due to small sample size, PSPRS subdomains were dichotomized, and t‐tests were performed to evaluate group differences based on symptom presence. Results Total mApp‐FTT taps on iOS and Android were strongly correlated ( r = 0.86, 95% CI [0.76, 0.92], p < .001). mApp‐FTT was associated with manual FTT on iOS ( r = 0.70, 95% CI [0.52, 0.82], p < .001) and Android ( r = 0.62, 95% CI [0.41, 0.77], p < .001). Among iOS users, total PSPRS score was negatively correlated with mApp‐FTT ( r = ‐0.60, 95% CI [‐0.75, ‐0.39], p < .001). Worse mApp‐FTT performance was observed in participants with higher limb rigidity (mean difference=15.46, 95% CI [3.40, 27.52], p < .001), limb dystonia (mean difference=19.22, 95% CI [5.67, 32.77], p < .001), and finger tapping (mean difference=12.74, 95% CI [3.42, 22.06], p < .001). Total UPDRS score correlated with lower mApp‐FTT ( r = ‐0.48, 95% CI [‐0.66, ‐0.28], p < .001), as did disease severity (CDR®+NACC‐FTLD Box Score; r=‐0.46, 95% CI [‐0.66, ‐0.22], p < .001). Conclusion Smartphone‐based finger‐tapping assessments effectively detect motor and cognitive impairment, with stronger associations for motor function. Findings in iOS users highlight the need to assess operating system‐related biases and validate in Android. Remote smartphone assessments offer a scalable tool for tracking disease progression, warranting larger longitudinal studies.

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

Abstract Background Staging disease severity in dementia research requires input from an informant. The Clinical Dementia Rating Sum of Boxes (CDR) is the most used instrument for staging in Alzheimer's Disease (AD); but has been expanded to stage patients with frontotemporal lobar degeneration (FTLD) with the CDR PLUS NACC‐FTLD. An informant effect on the CDR has been reported in AD. The aim of this study is to evaluate whether informant characteristics influence the CDR PLUS NACC‐FTLD in a large cohort of participants with frontotemporal dementia (FTD). Method We included participants with a FTLD‐related syndrome from the ALLFTD study. We included participants with a CDR PLUS NACC‐FTLD higher than 0, information on the Montreal Cognitive Assessment (MoCA) scores, and the Neuropsychiatric Inventory Questionnaire (NPI‐Q). We performed a conditional growth model using multilevel linear regression analysis. We performed an exploratory stratified analysis by patient sex. Result We included 1411 participants, totalling 2063 visits. The patient's age at the initial visit was 64.7±9.4 years and 44.0% were females. Females were 69.2% of the informants, and the relationship was 79.1% spouse or partner, 10.6% children, 4.1% were siblings and 6.2% other. The CDR PLUS NACC‐FTLD scores were affected by informant characteristics. The CDR PLUS NACC‐FTLD scores were 0.41 (CI 95%:0.08 to 0.75) higher with female informants. The frequency of visits was associated with a CDR PLUS NACC‐FTLD score 0.86 higher (CI 95%:0.17 to 0.56) when visiting at least once a week, 1.46 higher (CI 95%:0.46 to 2.47) when visiting daily, and 0.83 higher (CI 95%:0.06 to 1.60) when living with the patient compared with visiting less than once a week. As expected, CDR‐FLTD scores increased with lower MoCA and higher NPI‐Q scores. In the stratified analysis by sex, we found that female informant was associated with higher CDR PLUS NACC‐FTLD scores only when patients were male. Conclusion We found that the CDR PLUS NACC‐FTLD is influenced by informant sex and frequency of visits in patients with FTLD‐related syndromes. These results are similar to those observed in AD patients and underscore the need to recognize that informant characteristics may impact dementia severity scales.

Abstract Background Recent technological advances have enhanced the precision of blood‐based multiplex proteomics and their application in Alzheimer's disease. However, these approaches remain underutilized in frontotemporal lobar degeneration (FTLD). Familial FTLD cohorts offer a unique opportunity to study presymptomatic periods of disease that cannot be studied in sporadic cases. We leveraged NUcleic acid Linked Immuno‐Sandwich Assay (NULISAseq) to identify blood‐detectable proteins that change prior to symptom onset in familial FTLD. Method 120 FTLD mutation carriers (40 C9orf72 , 40 GRN , 40 MAPT ) and 40 age and sex‐matched noncarrier controls from the ALLFTD Consortium completed blood draws and clinical assessment. Targeted plasma proteomics was performed via NUcleic acid Linked Immuno‐Sandwich Assay (NULISAseq; 132 proteins). Disease age estimates measuring predicted symptom onset were derived from a validated model incorporating FTLD gene‐specific clinical, neuroimaging, and biomarker data. Mass linear regression models identified disease age ‘thresholds’ where individual proteins significantly diverged between each mutation carrier group and controls. NULISAseq targets were validated against orthogonal assays, specifically Simoa (plasma) and SomaScan (cerebrospinal fluid [CSF]). Result Compared to controls, 14 plasma proteins significantly diverged ( p <.05) in C9orf72 , 24 in GRN , and 13 in MAPT . Beyond NEFL, 10 additional proteins significantly diverged in more than one mutation group, including markers of synaptic function (NPTX2, NPTXR) and vascular integrity (PGF) that deviated prior to estimated symptom onset (disease age range: ‐30 to 0). Proteins with gene‐specific signals included GFAP (increased in GRN at disease age ‐17), ENO2 (decreased in C9orf72 at disease age ‐7), and FLT1 (increased in MAPT at disease age ‐6). Plasma NULISA‐based NEFL and GFAP showed strong concordance when measured via plasma Simoa ( r s>0.88) and were among 38 targets with significant concordance when measured via CSF SomaScan ( r range: 0.16 to 0.75, p s<.05). Conclusion Alterations in plasma protein abundance are measurable in familial FTLD prior to predicted symptom onset. The validity and brain‐based relevance of blood‐detectable NULISA targets is bolstered by the observed convergence with plasma Simoa and CSF SomaScan. Replication of top hits in larger familial and sporadic FTLD sample sizes is warranted to determine generalizability and suitability for clinical trials.