Graff‐Radford, Neill R.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

AbstractBackgroundDiffusion‐weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results.ObjectiveWe employed free‐water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB.MethodsBaseline and follow‐up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI‐LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative.ResultsWe followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between‐group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS‐UPDRS and MoCA scores.ConclusionsFW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

AbstractINTRODUCTIONPatients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease.METHODSThe cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI‐LB), or DLB, with a concurrent blood draw and PET scans.RESULTSAbnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI‐LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p‐tau)‐181 and neurofilament light (NfL) were found at the DLB stage. Plasma p‐tau‐181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB.DISCUSSIONThe range of AD co‐pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p‐tau‐181 and GFAP.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

AbstractBackgroundWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories.Method282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid‐negative EOnonAD (n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category (e.g., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test.ResultDemographic data are presented in Table 1. Average total NPI‐Q score was higher in EOnonAD than EOAD (p = .002, ŋp 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors (p = .02, OR = .498) and Impulse Control behaviors (p = .01, OR = .438). EOAD informants also endorsed apathy (p < .001, OR = .316), irritability (p = .02, OR = .498), and disinhibition (p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group (p = .002, ŋp 2 = .03). (Table 2A). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) (p = .03, Cohen W = .14) (Table 2B).ConclusionNPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators (e.g., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

AbstractBackgroundApproximately 10‐25% of amnestic early‐onset dementia are negative for amyloid (Early‐onset non‐Alzheimer’s Disease, EOnonAD). EOnonAD is a heterogenous group with various etiologies. In order to better understand the traits of EOnonAD, we clustered amnestic EOnonAD individuals according to cognitive patterns.MethodCognitive data of 62 EOnonAD individuals from the Longitudinal Early‐onset AD study (LEADS) were Z‐normalized to 91 intact individuals after adjusting for age, sex, and education. This led to domain‐averaged composite Z‐scores for memory, language, speed/attention, visuospatial, and executive function. Cluster analysis using the Ward method on the residuals for the five composites was performed. We used Scree plot using the pseudo T‐squared to determine the optimal number of clusters. We compared demographics, imaging biomarkers (amyloid and tau PET SUVR, hippocampal volume), plasma (pTau231, Aß40, Aß42, glial fibrillary acidic protein, and neurofilament light chain (NfL)), and cerebrospinal fluid (CSF) biomarkers (Aß42/40, NfL, Neurogranin, Visinin‐like protein, YKL‐40, and Synaptosome Associated Protein 25) across the clusters after adjusting for age, sex, and education. We compared gray matter density of each EOnonAD cluster to controls (n = 84) using voxel‐wise multiple linear regressions in SPM12, adjusting for age, sex, education, and intracranial volume.ResultScree plot using the pseudo‐T‐squared suggested three clusters. Cluster 1 (38/62, 61.3%) was characterized by having the mildest cognitive impairment in all domains. Cluster 2 (19/62, 30.6%) was characterized by more severe memory and language impairment. Cluster 3 (5/62, 8.1%) was characterized by more severe impairment in speed/attention, visuospatial, and executive function (Table 1). Cluster 3 showed significantly higher NfL for both plasma (Cluster 1 vs 3, p<0.001; Cluster 2 vs 3, p < 0.004) and CSF (Cluster 1 vs 3, p = 0.001). Other biomarkers did not show significant difference (Table 1). Only Cluster 3 showed significant atrophy in the bilateral fronto‐parietal areas at p<0.01, uncorrected (Figure 1).ConclusionWe identified heterogeneity in cognitive patterns among amnestic EOnonAD individuals. Cluster 1 had mildest cognitive impairment; Cluster 2 had predominant impairment in memory and language; and Cluster 3 had predominant impairment in speed/attention, visuospatial, and executive function, with significant fronto‐parietal atrophy and high NfL indicating active neurodegeneration.

AbstractBackgroundPlasma biomarkers such as Aβ 42/40 have emerged as important tools to detect dementia risk, although whether plasma Aβ 42/40 levels and the associations with dementia risk differ by race is unclear. As part of the Health, Aging, and Body Composition study, we compared the plasma levels of Aβ 42/40 ratio and the associations with 15‐year dementia risk by race among community‐dwelling Black and White older adults.MethodsWe studied 997 dementia‐free participants (55% women, 54% Blacks) aged 70‐79 years (mean age 74.5±2.9) enrolled at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations in the Modified Mini‐Mental State Examination score. Stored plasma obtained one year after baseline was used to measure Aβ with Innogenetics INNO‐BIA assays at Mayo Clinic, Jacksonville, FL. Plasma Aβ42/40 ratio was categorized into low, medium, and high tertiles. We used linear regression to estimate the difference in log‐transformed Aβ42/40 in Black and White participants and back‐transformed the effect estimates. We assess the association between Aβ42/40 (by tertiles) and dementia risk using Cox proportional hazards model stratified by race. All models were adjusted for age, sex, hypertension, diabetes, high cholesterol, and obesity, and we tested for interactions by race.ResultsBlack participants had significantly lower Aβ42/40 than White participants (‐4.4%, 95% CI ‐8.1% to ‐0.6%). In stratified analysis, lower Aβ42/40 was significantly associated with an increased risk of incident dementia among Black participants: 27.8% in medium (hazard ratio [HR] 1.69, 95% CI 1.07 to 2.68) and 33.5% in low (HR 2.07, 95% CI 1.32 to 3.24) compared with 17.3% in high Aβ42/40 tertile. The associations were somewhat weaker but showed the same trend among White participants: 20.3% in medium (HR 1.49, 95% CI 0.85 to 2.61) and 22.9% in low (HR 1.59, 95% CI 0.92 to 2.76) compared with 15% in high Aβ42/40 tertile. The interaction between Aβ42/40 and race was not statistically significant.ConclusionAmong community‐dwelling, non‐demented older adults, plasma Aβ42/40 differs by race, although the association with dementia risk does not differ by race.

AbstractBackgroundAfrican Americans experience a high dementia burden yet are critically underrepresented in observational studies and clinical trials in memory and aging. Lack of adequate representation increases the likelihood that research findings may not generalize to African Americans. A deeper understanding of the barriers and facilitators that influence participation by younger and older African American adults is needed to support recruitment and retention in studies focused on early‐ and late‐onset neurodegenerative diseases.MethodAfrican American community leaders collaborated in design of an electronic survey that was distributed via social media focused on local zip codes. Survey respondents rated barriers and facilitators to research participation on a 0–3‐point Likert scale. Responses ≥2 corresponded with barriers/facilitators likely to influence participation decisions. Differences across age groups were evaluated using nonparametric Kruskal‐Wallis tests. Strategies to mitigate barriers and reinforce facilitators were further explored via community‐based focus groups.ResultSurvey data included responses from 240 African Americans (18‐44‐years, n = 76; 45‐64‐years, n = 83; ≥65‐years, n = 81). Requirement to undergo a diagnostic lumbar puncture was a substantial barrier to research participation across all age groups. Attending weekday visits (median = 2.0), including visits ≥2 hours (median 2.0), was a substantial barrier for individuals 18‐44‐years, but not older respondents (p = 0.001). Compensation for meals/transportation was beneficial across all age groups (median = 2.0; p<0.05). The option to attend visits in the local community or on weekends and access to door‐to‐door transportation were substantial facilitators for respondents <65‐years (median = 2.0) vs ≥65‐years (median = 0; p = 0.001). The option to complete some tests at home was a substantial facilitator for younger (18‐44‐years, median = 2.0) but not older respondents (≥65‐years, median = 0; p = 0.001). Focus group results supported survey findings and showed slight variations in priorities across age groups. Older participants (≥65‐years‐old) more frequently cited the longstanding effects of racism as a barrier to research participation compared to younger participants (45‐64‐years‐old; p = 0.008), who more frequently cited concerns regarding testing requirements (p = 0.034).ConclusionPerceived barriers and facilitators to research participation vary with age. Age‐specific strategies are needed to increase engagement, address disparities in recruitment, and promote retention of African American participants in studies of memory and aging across the lifespan.

AbstractBackgroundPerturbations in immune pathways are strongly associated with Alzheimer’s disease. A positive association between autoimmune diseases and frontotemporal dementia has been reported. We explored whether early onset Alzheimer’s disease (EOAD) would associate with autoimmune diseases.MethodWe compared 313 patients with EOAD from the Mayo Clinic Florida, Alzheimer’s Disease Research Center (ADRC) Registry with matched cognitively normal controls (NC) based on age (+/‐ 2 years) and gender at 1:2 ratio. NC were derived from Mayo Clinic Biobank Project, Rochester (N = 313) and the Mayo Clinic Study of Aging (N = 313). Data abstraction was performed by trained statisticians using ICD 9&10 codes corresponding to 40 specified autoimmune diseases and/or documentation of specified immunomodulatory treatment. Data was also abstracted via retrospective record review. We further reviewed clinical records from EOAD patients with neuropathologically confirmed Alzheimer’s disease patients enrolled in the ADRC (n = 10). Each autoimmune disease type was compared between cases and controls using Fisher’s exact test. All tests were two‐sided with alpha level set at 0.05 for statistical significance. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The prevalence of autoimmune disease in the general population was based off Hayter & Cook, 2012 and Roberts & Erdei, 2020. All data abstraction was done blinded to the clinical diagnosis and baseline demographics.ResultAutoimmune disease history was abstracted from 949 patient records (313 EOAD, 10 pathologically‐confirmed EOAD, 626 NCI). The median age was 57 years‐old. (EOAD range 28,65 yrs.; NC 30,66 yrs.). Autoimmune thyroiditis (p = 0.0008), ulcerative colitis (p = 0.011, psoriasis (<0.0001), rheumatoid arthritis (p = 0.0005), and Raynaud’s syndrome (p = 0.0021) were less prevalent in patients with EOAD compared to NC. Furthermore, patients with EOAD had a lower prevalence of immune mediated hematologic disorders.ConclusionPatients with EOAD have a lower prevalence of autoimmune diseases than NC. Immune activation identified in early onset AD patients may be unrelated to autoimmunity. Findings should be explored in late onset AD patients.