Miller, Bruce L.

AbstractINTRODUCTIONWhile Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care.METHODSIn 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm.RESULTSSignificant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted.DISCUSSIONThe myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Abstract Approximately 5% of Alzheimer’s disease patients develop symptoms before age 65 (early-onset Alzheimer’s disease), with either sporadic (sporadic early-onset Alzheimer’s disease) or dominantly inherited (dominantly inherited Alzheimer’s disease) presentations. Both sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer’s disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer’s disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50–70 cerebellar grey reference and FDG30–60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer’s disease, sporadic early-onset Alzheimer’s disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer’s disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer’s disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer’s disease versus sporadic early-onset Alzheimer’s disease. Sporadic early-onset Alzheimer’s disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer’s disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer’s disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer’s disease.

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.

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.

AbstractBackgroundPresymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking.MethodLeveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only).ResultWe found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN.ConclusionDespite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers.

AbstractBackgroundPresymptomatic C9orf72 expansion carriers show regions of low local gyrification index (lGI) as early as their thirties (Caverzasi et al. JNNP 2019) and regions of gyrification decline have been reported (van Veenhuijzen et al. Ann Neurol 2022). These findings raise the question as to whether abnormal gyrification represents a neurodevelopmental difference or early neurodegeneration in frontotemporal lobar degeneration (FTLD) mutation carriers. Yet, previous studies focusing on young adults is lacking and no study has explored gyrification in the two other common FTLD mutations, GRN and MAPT. Here, we analyzed lGI in young adult presymptomatic FTLD mutation carriers.MethodLGI quantifies buried cortex within the sulcal folds compared to the visible cortex on the outer surface, with larger values indicating more folding (Schaer et al. IEEE trans med imaging 2008). Mean lGI values, as measured by a parcel‐wise analysis implemented in FreeSurfer v.6.0, were compared between 31 presymptomatic (preSx) carriers (12 C9orf72, 13 MAPT, 6 GRN, mean age: 25.2 ± 3.91 years) and 28 demographically‐matched healthy controls (HC: mean age: 25.6 ± 3.8 years). We used ANCOVA to compare all presymptomatic carriers combined (preSxAll) and HC to identify regions with significant lGI differences regressing age, sex, education, handedness, total intracranial volume and scanner type as nuisance covariates. Significant group differences were analyzed by Dunnett’s post‐hoc tests between each mutation subgroup and HC (p<0.05).ResultCompared to HC, preSxAll had higher mean gyrification in the right caudal (F = 5.07, p = 0.03) and rostral anterior cingulate (F = 6.22, p = 0.17), and lower lGI in the left middle temporal gyrus (F = 4.22, p = 0.046). Within these regions, post‐hoc analyses showed that preSx GRN had greater gyrification in the right caudal anterior cingulate (t = 2.57, p = 0.039, 95% CI = [0.005, 0.248]) and preSx C9orf72 had lower lGI in the left middle temporal gyrus (t = ‐3.14, p = 0.009, 95% CI = [‐0.37, ‐0.04]) vs. HC.ConclusionYoung adult FTLD mutation carriers displayed higher gyrification in the right anterior cingulate and lower gyrification in the left middle temporal gyrus compared to HC. Future studies in children will confirm the extent to which these gyrification abnormalities represent neurodevelopmental differences.

AbstractBackgroundThe pathophysiological mechanisms driving frontotemporal lobar degeneration (FTLD) disease progression and corresponding biomarkers that capture these changes are not fully understood. We leveraged high‐throughput proteomics to identify networks of co‐expressed CSF proteins and candidate biomarkers for prediction of disease progression in adults with autosomal dominant FTLD mutations.Method113 adults carrying autosomal dominant FTLD mutations (C9orf72/GRN/MAPT) and 38 noncarrier controls from the ALLFTD consortium completed baseline lumbar puncture and longitudinal neuropsychological testing. CSF was assayed for SOMAmer proteomics on SOMAscan® v3.0 (4,140 proteins). Network analysis identified weighted protein co‐expression modules, which were annotated via gene ontology and cell‐type enrichment analysis. Disease age estimates that capture proximity to symptom onset were derived from a Bayesian disease progression model incorporating genotype‐specific clinical (cognition, CDR®+NACC FTLD) and biomarker (brain volume, plasma NfL) information. At baseline, local‐weighted regression examined module z‐scores (based on mean/SD of module levels [first principal component] in noncarriers) in relation to disease age. Longitudinal linear mixed‐effects models examined global cognitive trajectories in relation to baseline module z‐scores, as well as individual proteins within prognostic modules.ResultNetwork analysis identified 32 CSF protein co‐expression modules (37 to 223 proteins/module). 16 modules showed mutation‐related deviations from noncarriers. Deviations in ion transport, neurodevelopmental, metabolic, and transcriptional modules occurred several decades before estimated symptom onset (disease age: ‐30 to ‐20 years) and persisted across disease age. Deviations in neuroinflammatory and ubiquitination/autophagy modules occurred ∼10 years before estimated symptom onset. Sharp deviations in RNA binding, protein phosphorylation, neurogenesis, synaptic function, and lysosomal modules occurred near symptom onset (disease age: ‐1 to 4 years). Baseline synaptic and neurogenesis modules were the strongest prognosticators of cognitive decline (module x time: bs>.10, ps<.05). Within these modules, individual proteins with stronger intramodular connectivity exhibited stronger associations with cognitive decline (e.g., synaptic/transmembrane module: r = .40, p = 2.85e‐6; e.g., EPHA5, LRRTM2).ConclusionLarge‐scale analysis of the CSF proteome reveals a biologically‐diverse landscape of protein networks associated with presymptomatic and symptomatic stages of autosomal dominant FTLD. Synaptic and neuron‐enriched protein networks exhibited prodromal deviations that forecasted incipient cognitive decline. ‘Hub’ proteins derived from these affected networks warrant further validation as candidate biomarkers for early FTLD disease progression.

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.