Lee, Hyunwoo

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.

Background Neuropsychiatric symptoms (NPS) progress differently among individuals with autosomal dominant familial frontotemporal dementia (FTD) caused by genetic mutations in granulin ( GRN +) or chromosome 9 open reading frame 72 ( C9orf72 +). Objective To determine whether these differences begin prior to the onset of dementia, we compared the longitudinal rates of change of NPS among C9orf72 +, GRN +, and noncarrier controls in the predementia phase. Additionally, we assessed whether the NPS changes were correlated with gray matter (GM) volume loss or white matter signal abnormalities (WMSAs) on magnetic resonance imaging (MRI). Methods Eighty-two participants (N = 10 GRN +, N = 23 C9orf72 +, N = 49 noncarriers) were followed using various NPS rating scales for an average of 7.8 years. Group differences were compared using generalized linear mixed-effects models. GM volume and WMSA volumes were measured on 42 participants (N = 8 GRN +, N = 11 C9orf72 +, N = 23 noncarriers) who had two MRI visits. These measures were correlated with the rates of NPS score changes. Results C9orf72 + showed higher rates of increase in the Beck Depression Inventory (BDI) total and the Iowa Scales of Personality Change (ISPC) dysexecutive disturbance scores versus noncarriers. GRN + showed higher rates of increase in the BDI total, the ISPC total, and the emotional/social disturbance scores versus noncarriers; and higher rates of increase in the ISPC emotional/social personality and distressed disturbance scores versus C9orf72 +. Across all groups, faster WMSA accumulation correlated with higher rates of increase in the Neuropsychiatric Inventory Questionnaire total score. Conclusions Changes in NPS differ among C9orf72 +, GRN +, and noncarrier controls prior to the onset of overt FTD.

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.

AbstractBackgroundNeuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.ResultWe analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.ConclusionPrior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+=47, GRN+=56, MAPT+=40, controls=47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p=0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.

AbstractA large proportion of familial frontotemporal dementia is caused by TAR DNA-binding protein 43 (transactive response DNA-binding protein 43 kDa) proteinopathies. Accordingly, carriers of autosomal dominant mutations in the genes associated with TAR DNA-binding protein 43 aggregation, such as Chromosome 9 open reading frame 72 (C9orf72) or progranulin (GRN), are at risk of later developing frontotemporal dementia. Brain imaging abnormalities that develop before dementia onset in mutation carriers may serve as proxies for the presymptomatic stages of familial frontotemporal dementia due to a genetic cause. Our study objective was to investigate brain MRI-based white-matter changes in predementia participants carrying mutations in C9orf72 or GRN genes. We analysed mutation carriers and their family member controls (noncarriers) from the University of British Columbia familial frontotemporal dementia study. First, a total of 42 participants (8 GRN carriers; 11 C9orf72 carriers; 23 noncarriers) had longitudinal T1-weighted MRI over ∼2 years. White-matter signal hypointensities were segmented and volumes were calculated for each participant. General linear models were applied to compare the baseline burden and the annualized rate of accumulation of signal abnormalities among mutation carriers and noncarriers. Second, a total of 60 participants (9 GRN carriers; 17 C9orf72 carriers; 34 noncarriers) had cross-sectional diffusion tensor MRI available. For each participant, we calculated the average fractional anisotropy and mean, radial and axial diffusivity parameter values within the normal-appearing white-matter tissues. General linear models were applied to compare whether mutation carriers and noncarriers had different trends in diffusion tensor imaging parameter values as they neared the expected age of onset. Baseline volumes of white-matter signal abnormalities were not significantly different among mutation carriers and noncarriers. Longitudinally, GRN carriers had significantly higher annualized rates of accumulation (estimated mean: 15.87%/year) compared with C9orf72 carriers (3.69%/year) or noncarriers (2.64%/year). A significant relationship between diffusion tensor imaging parameter values and increasing expected age of onset was found in the periventricular normal-appearing white-matter region. Specifically, GRN carriers had a tendency of a faster increase of mean and radial diffusivity values and C9orf72 carriers had a tendency of a faster decline of fractional anisotropy values as they reached closer to the expected age of dementia onset. These findings suggest that white-matter changes may represent early markers of familial frontotemporal dementia due to genetic causes. However, GRN and C9orf72 mutation carriers may have different mechanisms leading to tissue abnormalities.