Early-onset Alzheimer's disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer's Disease Study (EOAD; n=390) and Alzheimer's Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD.

INTRODUCTION:Although cerebrospinal fluid (CSF) biomarkers reflect neurodegeneration in Alzheimer's disease (AD), it remains unclear whether these biomarkers track neurodegeneration in early-onset Alzheimer's disease (EOAD). METHODS:In 80 EOAD patients, we examined correlations between eight CSF biomarker levels and cortical thickness decreases within the EOAD cortical atrophy signature. Significant correlations were then entered into a multiple regression analysis. We also examined contributions of EOAD atrophy and CSF biomarkers to cognitive impairment. RESULTS:The levels of four CSF biomarkers correlated to EOAD signature atrophy. Stepwise regression analyses revealed that CSF neurofilament light chain (NfL) levels best predicted EOAD signature atrophy. Multiple regression showed EOAD signature atrophy combined with CSF NfL levels explained more variance in cognitive impairment than either factor alone. DISCUSSION:Within EOAD patients, CSF NfL levels relate to the magnitude of cortical atrophy, and a combination of EOAD signature atrophy and CSF NfL levels most robustly predict cognitive impairment.

OBJECTIVE:Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f-FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f-FTLD. We used a Bayesian linear mixed-effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. METHODS:Participants included 234 asymptomatic or prodromal carriers of C9orf72, GRN, or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1-weighted scans. The BLME models established individual voxel-wise gray matter trajectories using the first 2 scans. Person-specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time-varying Cox proportional hazard models covarying for age. Receiver-operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. RESULTS:The BLME cluster volume predicted conversion to dementia in f-FTLD mutation carriers overall and separately in C9orf72, GRN, and MAPT, with comparable hazard ratios observed for atrophy W-maps and regional volumes. Within a 24-month timeframe, BLME cluster volume discriminated dementia converters from non-converters with larger areas under the curve (AUCs) than other approaches. INTERPRETATION:Bayesian-modeled individualized atrophy scores predict dementia progression among asymptomatic f-FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a-n/a.

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.

OBJECTIVE:Autosomal dominant progranulin (GRN) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. METHODS:Utilizing T1 and task-free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole-brain degree, and GRN-relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive-compulsive disorder symptom severity, and gray matter volume. RESULTS:Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive-compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN-frontotemporal dementia. INTERPRETATION:In asymptomatic carriers, the co-occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Background:While understanding how corticostriatal connectivity is associated with socioeconomic status (SES), trauma exposure, cognitive function, reward salience, impulsivity, and future substance use is essential to identifying neurobiological pathways that contribute to health disparities and behavioral outcomes, very few studies have tested the role of left caudate resting-state functional connectivity (rsFC) with the cingulo-opercular network as a proxy of corticostriatal connectivity in social, cognitive, and behavioral processes. Objective:This study investigates the associations between left caudate-cingulo-opercular connectivity and multiple biopsychosocial domains, including low SES, high trauma exposure (financial and life events), cognitive function, reward salience, impulsivity, depression, and future substance use (tobacco and marijuana use). Methods:Resting-state functional magnetic resonance imaging (rs-fMRI) data were analyzed to assess connectivity between the left caudate and the cingulo-opercular network. Data on socioeconomic status, trauma exposure, cognitive performance, and mental health were collected from participants. Future substance use behaviors were evaluated through longitudinal follow-ups. Correlation and regression analyses were conducted to examine relationships between corticostriatal connectivity and the targeted domains. Results:Corticostriatal hypoconnectivity was associated with lower SES, higher trauma exposure, poorer cognitive function, heightened reward salience, higher impulsivity, and history of depression. Additionally, corticostriatal hypoconnectivity at baseline predicted future tobacco and marijuana use during follow-up years. Conclusion:Corticostriatal hypoconnectivity, particularly the rsFC between the left caudate and the cingulo-opercular network, may represent a potential mechanism linking a wide range of social, emotional, and behavioral problems in youth. These findings suggest that corticostriatal hypoconnectivity could serve as a neurobiological marker for identifying individuals at risk for depression, low cognitive function, high reward salience, impulsivity, and substance use, emphasizing the interplay between socioeconomic and neurocognitive factors in shaping behavioral health trajectories.

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.

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). 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. 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. 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.

Background:The Cingulo-Opercular Network (CON) is a crucial executive control network involved in regulating actions and facilitating higher-order cognitive processes. Resting-state functional connectivity between the CON and the Default Mode Network (DMN) plays a vital role in cognitive regulation, enabling the transition between internally focused and externally directed tasks. This study investigates whether resting-state functional connectivity between the CON and DMN mediates the effects of social determinants, such as educational opportunities and family structure, on cognitive outcomes in youth. Aims:This study aims to explore how CON-DMN connectivity influences the relationship between social gradients and cognition in youth. Specifically, it examines whether resting-state functional connectivity between these networks mediates the effects of educational opportunities and family structure on cognitive outcomes and seeks to uncover the neural mechanisms underlying these social gradients. Methods:Data were derived from the Adolescent Brain Cognitive Development (ABCD) study, a large longitudinal dataset of over 11,000 children aged 9-10 years. Cognitive outcomes were assessed using standardized NIH toolbox measures: Total Composite, Fluid Reasoning, Picture Vocabulary, Pattern Recognition, and Card Sorting. Social determinants were operationalized using indicators such as parental education, family composition, and neighborhood educational opportunities (COI). Resting-state functional connectivity (rsFC) between the CON and DMN was measured using functional magnetic resonance imaging (fMRI). Structural equation modeling (SEM) was employed to test whether CON-DMN rsFC mediated the relationship between social determinants and cognitive outcomes, adjusting for potential confounders such as age, sex, and race/ethnicity. Results:Stable family structure and greater educational opportunities were significantly associated with improved cognitive performance. These relationships were mediated by reduced functional connectivity between the CON and DMN. Conclusion:Reduced functional connectivity between the CON and DMN serves as a neural mechanism linking social gradients, such as educational opportunities and family structure, to better cognitive outcomes in youth.

INTRODUCTION:Early-onset and late-onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head-to-head comparison of cortical atrophy in EOAD and LOAD, using two large and well-characterized cohorts (LEADS and ADNI). METHODS:We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early-stage AD), along with cognitively unimpaired participants. RESULTS:After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION:Our findings point to the clinical utility of MRI-based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. HIGHLIGHTS:Early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

Hate toward people groups is a significant cause of human suffering, yet we understand relatively little about its neurocognitive and neuroanatomical bases. While definitions of hate vary, most agree that it can be defined as an aversion to certain others that motivates attempts to expel them through methods ranging from physical violence to passive avoidance. The evolutionary roots of group hate are in the ingroup-outgroup distinction, in which the individual favors ingroup members over outgroup members. Earlier studies on the effects of hate speech and propaganda show that the dehumanization of outgroup members facilitates hate. Although several mechanisms have been proposed, evidence suggests that dehumanization leads to hate due to the perceived failure of outgroup members to meet a moral ideal of right and wrong. As such, hate can be understood as an innate moral sentiment that enhances themes of ingroup loyalty and purity by expelling the offending outgroup. It involves regions of the brain active in social cognition, emotion, empathy, and behavioral regulation, such as the medial prefrontal cortex, inferior frontal gyrus, anterior cingulate cortex, amygdala, insula, and temporoparietal junction. By examining these neurobiological aspects of hate and understanding them in the context of the social and cultural factors that foster hate, we can gain deeper insights into this harmful phenomenon and how best to combat it.

Background:The sensory-motor network is essential for integrating sensory input with motor function and higher-order cognition. Resting-state functional connectivity (rsFC) within this network undergoes significant developmental changes, and disruptions in these connections have been linked to behavioral and psychiatric outcomes. However, the relationship between sensory-motor connectivity, early-life adversity, and later health behaviors remains understudied. Objective:This study examines the associations between rsFC within the sensory-motor network (mouth and hand regions) and key social, psychological, and behavioral factors, including baseline and past socioeconomic status (SES), trauma exposure, family conflict, impulsivity, major depressive disorder (MDD), and future substance use. Methods:Data were drawn from the Adolescent Brain Cognitive Development (ABCD) Study, a national sample of U.S. children. Resting-state fMRI data were used to assess functional connectivity within the sensory-motor network. Bivariate analyses examined associations between rsFC in the sensory-motor mouth and hand regions and baseline SES, past SES, childhood trauma exposure, family conflict, impulsivity, and MDD. Longitudinal analyses assessed whether baseline rsFC predicted future substance use. Results:Greater rsFC between the sensory-motor mouth and hand regions was significantly associated with lower SES, higher trauma exposure, and greater family conflict. Increased connectivity was also correlated with older age and more advanced puberty status. Higher rsFC between the sensory-motor mouth and hand regions was linked to greater impulsivity, lower cognitive function, an increased likelihood of MDD, and future marijuana use. Conclusion:These findings suggest that sensory-motor connectivity is sensitive to socioeconomic and psychosocial stressors, with potential long-term implications for mental health and substance use risk. The results highlight the importance of early-life environmental factors in shaping neurodevelopmental trajectories and emphasize the need for targeted interventions to mitigate the effects of adversity on brain function and behavior. Future research should further explore the role of sensory-motor network alterations in behavioral health outcomes as a function of environmental stressors.

Background:The hippocampus plays a critical role in memory and decision-making processes, with its resting-state functional connectivity (rsFC) linked to various behavioral outcomes. This study investigates whether baseline brain-wide rsFC of the hippocampus mediates the relationship between impulsivity and subsequent substance use, specifically tobacco and marijuana use, in adolescents. Methods:Data were drawn from the baseline wave of the Adolescent Brain Cognitive Development (ABCD) study. Resting-state fMRI data were used to evaluate the functional connectivity of the hippocampus with key brain networks, including the cingulo-parietal network, visual network, sensory-motor network, and default mode network (DMN). Impulsivity was assessed using validated self-report measures, and substance use (tobacco and marijuana) was evaluated at follow-up. Mediation models were conducted to examine the extent to which hippocampal rsFC explains the association between impulsivity and substance use. Results:Baseline hippocampal rsFC with the cingulo-parietal network, visual network, sensory-motor network, and DMN showed marginal associations with future tobacco and marijuana use. Additionally, hippocampal rsFC was significantly associated with impulsivity, which, in turn, predicted higher substance use at follow-up. These findings suggest that hippocampal rsFC partially mediates the relationship between impulsivity and substance use behaviors. Conclusions:Hippocampal functional connectivity with brain networks may influence the pathway from impulsivity to future substance use in adolescence. These findings emphasize the importance of hippocampal connectivity in understanding the neural mechanisms underlying risk behaviors and may inform the development of targeted interventions to reduce substance use in this vulnerable population.

Background Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. Objective To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). Method We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. Result LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. Conclusion We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders.

Background Understanding experiences and challenges faced by persons living with Early-Onset Dementia (EOD) compared to individuals diagnosed with Late-Onset Dementia (LOD) is important for the development of targeted interventions. Objective Describe differences in sociodemographic, neuropsychiatric behavioral symptoms, caregiver characteristics, and psychotropic use. Design, Setting, Participants Cross-sectional, retrospective study including 908 UCLA Alzheimer's Dementia Care Program participants (177 with EOD and 731 with LOD). Measurements Onset of dementia was determined using age at program enrollment, with EOD defined as age <65 years and LOD defined as age >80 years. Sociodemographic and clinical characteristics were measured once at enrollment. Behavioral symptoms were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score and caregiver distress was measured using the NPI-Q distress score. Medications included antipsychotic, antidepressant, benzodiazepines and other hypnotics, antiepileptics, and dementia medications. Results EOD compared to LOD participants were more likely men, college graduates, married, live alone, and have fewer comorbidities. EOD caregivers were more often spouses (56% vs 26%, p<0.01), whereas LOD caregivers were more often children (57% vs 10%, p<0.01). EOD was associated with lower odds of being above the median (worse) NPI-Q severity (adjusted odds ratio [aOR], 0.58; 95% CI 0.35-0.96) and NPI-Q distress scores (aOR, 0.53; 95% CI 0.31-0.88). Psychotropic use did not differ between groups though symptoms were greater for LOD compared to EOD. Conclusion Persons with EOD compared to LOD had sociodemographic differences, less health conditions, and fewer neuropsychiatric symptoms. Future policies could prioritize counseling for EOD patients and families, along with programs to support spousal caregivers of persons with EOD.

BACKGROUND AND OBJECTIVES:TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS:Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS:The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION:We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. ObjectiveThis study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. MethodsParticipants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants’ smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. ResultsThe CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). ConclusionsThese findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

INTRODUCTIONPsychotropic medication (PM) use in behavioral-variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD.METHODSWe analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART).RESULTSWe included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants.DISCUSSIONParticipants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated.Highlights We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD.

Importance Frontotemporal 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. Objective To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants In 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 Measures Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results In 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 beta 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 beta = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (beta = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance The 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.

INTRODUCTION:Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS:We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS:The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION:The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS:We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.