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IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Mario F Mendez1–3 1Department of Neurology, 2Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; 3Neurology Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA Abstract: Studies suggest a relationship of manic behavior and bipolar disorder (BD) with behavioral variant frontotemporal dementia (bvFTD). The nature of this relationship is unclear. This report presents a patient with initial manic behavior as the main manifestation of familial bvFTD from a novel progranulin (GRN) mutation. In contrast, there are other reports of a long background of BD preceding a diagnosis of bvFTD. A review of the literature and this patient suggest that manic symptoms result from damage to right frontotemporal neural structures from longstanding BD, as well as from bvFTD and other focal neurological disorders. In addition, there is a subgroup of patients with a probable genetic predisposition to both BD and bvFTD. Keywords: frontotemporal dementia, mania, bipolar disorder, progranulin mutation

Objective: The prevalence of dementia in northern India is among the lowest in the world but reasons are unclear. The aim of the study was to evaluate the risk and protective factors for dementia in North India. Methods: In a case-control study, we investigated demographic, medical, genetic, dietary, lifestyle, and sociocultural protective and risk factors associated with dementia. Results: 150 patients of dementia (118 males and 32 females) and 150 healthy controls (112 males and 38 females) were included in the study. Diabetes, depression, hyperhomocysteinemia, hyperlipidemia, APOE 4 gene, BMI, use of saturated fatty acids, pickles in diet, urban living, and lack of exercise were associated with independent risk of dementia. Various dietary factors and sociocultural factors, like cognitively stimulating activities, active socialization, living in joint families, increased intake of polyunsaturated fats, fruits, and salads conferred protection against dementia. Conclusions: Dietary, lifestyle, and sociocultural interventions may be protective against dementia. [ABSTRACT FROM AUTHOR]

Early-onset dementia (EOD, < 65 years at onset) is a relatively common and frequently misdiagnosed condition. One reason for misdiagnosis is that EOD has a more varied differential diagnosis than late-onset dementia (LOD). For example, Alzheimer's disease (AD), the preponderant LOD, makes up only about one-third of EODs; the rest are due to vascular dementias, frontotemporal lobar degenerations, traumatic head injury, alcohol-related dementia, and a great many other conditions. Another reason for misdiagnosis is that early-onset AD may have predominant cognitive deficits other than memory loss and a potential familial inheritance with spastic paraparesis, seizures, or myoclonus. A third reason is that EOD often presents with neuropsychiatric features out-of-proportion to any cognitive deficits. Despite these obstacles, it is important to accurately diagnose EODs, particularly because they differ in management and course. Clinicians can successfully diagnose most EODs with careful cognitive and family histories, mental status and neurological examinations, and neuroimaging. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD.Objective: To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging.Methods: 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion.Results: The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. "Moria" or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion.Conclusions: Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non-verbal behaviour. [ABSTRACT FROM AUTHOR]

Epileptic seizures occur in patients with dementia at a higher prevalence than among healthy elderly individuals. The incidence of seizures among patients with dementia varies with the aetiology of the dementing illness. In patients with Alzheimer's disease (the most common form of dementia), approximately 10-22% have at least one unprovoked seizure. Seizures usually occur in later stages of Alzheimer's disease, on average, > or =6 years into the course of the disease. Seizures in Alzheimer's disease are more likely to occur with early-onset disease, particularly if there is a familial presenilin I mutation. The incidence of seizures in other dementing diseases is less clear. There are special considerations regarding the management of seizures in the elderly with dementia. First, the presence of cognitive impairment may impede an accurate diagnosis of seizures. Clinicians may also mistake seizure manifestations for symptoms of the underlying dementia. Second, since most dementia patients are elderly, there are pharmacokinetic changes with aging that affect the use of antiepileptic drugs. Third, antiepileptic drugs have potential cognitive adverse effects that may worsen dementia. Although few studies are available, extrapolations from research in young people and elderly patients without dementia provide several recommendations for the management of seizures in patients with dementia: exclude symptomatic causes of seizures before committing to antiepileptic drug therapy; treat after a first seizure if there is evidence of focal neurological involvement or a risk of recurrent seizures; use antiepileptic drugs with minimal cognitive adverse effects, such as carbamazepine, valproic acid, gabapentin and lamotrigine; and use the lowest possible dosage and monitor antiepileptic drug levels, where possible. [ABSTRACT FROM AUTHOR]

Focuses on the clinical case of a patient with frontotemporal dementia (FTD) who developed prominent self-injurious behavior (SIB). Diagnosis of FTD; Potential mechanisms for SIB; Etiology of SIB.

Describes a traumatic brain injury patient who developed episodes of depression and mania after his injuries and reviews the literature on post-traumatic bipolar syndrome. Reported cases of post-traumatic bipolar syndromes; Demonstration of a diffused right hemisphere volume loss; Image of the right anterior inferior frontal and right anterior temporal lobe encephalomalacia.

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.

Introduction: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD)., Methods: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing., Results: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories., Discussion: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD., Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2024. The Author(s).)

Objective: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD)., Methods: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images., Results: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex., Conclusions: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD., Competing Interests: The authors report no financial relationships with commercial interests.

The intricate communication between plastids and the nucleus, shaping stress-responsive gene expression, has long intrigued researchers. This study combines genetics, biochemical analysis, cellular biology, and protein modeling to uncover how the plastidial metabolite MEcPP activates the stress-response regulatory hub known as the Rapid Stress Response Element (RSRE). Specifically, we identify the HAT1/TPL/IMPα- 9 suppressor complex, where HAT1 directly binds to RSRE and its activator, CAMTA3, masking RSRE and sequestering the activator. Stress-induced MEcPP disrupts this complex, exposing RSRE and releasing CAMTA3, while enhancing Ca 2+ influx and raising nuclear Ca 2+ levels crucial for CAMTA3 activation and the initiation of RSRE- containing gene transcription. This coordinated breakdown of the suppressor complex and activation of the activator highlights the dual-channel role of MEcPP in plastid-to- nucleus signaling. It further signifies how this metabolite transcends its expected biochemical role, emerging as a crucial initiator of harmonious signaling cascades essential for maintaining cellular homeostasis under stress., Summary: This study uncovers how the stress-induced signaling metabolite MEcPP disrupts the HAT1/TPL/IMPα-9 suppressor complex, liberating the activator CAMTA3 and enabling Ca 2+ influx essential for CAMTA3 activation, thus orchestrating stress responses via repressor degradation and activator induction.

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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Frontotemporal 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., Objective: This 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., Methods: Participants 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., Results: The 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)., Conclusions: These 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., (©Emily W Paolillo, Kaitlin B Casaletto, Annie L Clark, Jack C Taylor, Hilary W Heuer, Amy B Wise, Sreya Dhanam, Mark Sanderson-Cimino, Rowan Saloner, Joel H Kramer, John Kornak, Walter Kremers, Leah Forsberg, Brian Appleby, Ece Bayram, Andrea Bozoki, Danielle Brushaber, R Ryan Darby, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Fanny Elahi, Julie A Fields, Nupur Ghoshal, Neill Graff-Radford, Matthew G H Hall, Lawrence S Honig, Edward D Huey, Maria I Lapid, Irene Litvan, Ian R Mackenzie, Joseph C Masdeu, Mario F Mendez, Carly Mester, Toji Miyagawa, Georges Naasan, Belen Pascual, Peter Pressman, Eliana Marisa Ramos, Katherine P Rankin, Jessica Rexach, Julio C Rojas, Lawren VandeVrede, Bonnie Wong, Zbigniew K Wszolek, Bradley F Boeve, Howard J Rosen, Adam L Boxer, Adam M Staffaroni, ALLFTD Consortium. Originally published in JMIR Aging (https://aging.jmir.org), 26.06.2024.)

Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists. To address this, we performed a suppressor screen of the ceh1 mutant, which contains elevated 2-C-methyl-d-erythritol-2,4-cyclopyrophosphate (MEcPP) levels, and identified the gain-of-function mutant impα-9, which shows reversed dwarfism and suppressed expression of stress-response genes in the ceh1 background despite heightened MEcPP. Subsequent genetic and biochemical analyses established that the accumulation of MEcPP initiates an upsurge in Arabidopsis SKP1-like 1 (ASK1) abundance, a pivotal component in the proteasome degradation pathway. This increase in ASK1 prompts the degradation of IMPα-9. Moreover, we uncovered a protein-protein interaction between IMPα-9 and TPR2, a transcriptional co-suppressor and found that a reduction in IMPα-9 levels coincides with a decrease in TPR2 abundance. Significantly, the interaction between IMPα-9 and TPR2 was disrupted in impα-9 mutants, highlighting the critical role of a single amino acid alteration in maintaining their association. Disruption of their interaction results in the reversal of MEcPP-associated phenotypes. Chromatin immunoprecipitation coupled with sequencing analyses revealed that TPR2 binds globally to stress-response genes and suggested that IMPα-9 associates with the chromatin. They function together to suppress the expression of stress-response genes under normal conditions, but this suppression is alleviated in response to stress through the degradation of the suppressing machinery. The biological relevance of our discoveries was validated under high light stress, marked by MEcPP accumulation, elevated ASK1 levels, IMPα-9 degredation, reduced TPR2 abundance, and subsequent activation of a network of stress-response genes. In summary, our study collectively unveils fresh insights into plant adaptive mechanisms, highlighting intricate interactions among retrograde signaling, the proteasome, and nuclear transport machinery., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

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., Exposure: Participants 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 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 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.

Background: High educational attainment may protect individuals, particularly middle-aged and older adults, against a wide range of health risks, including memory decline with age; however, this protection is less clear in patients with Alzheimer's disease (AD). In addition, this effect may differ across racial groups. According to the Marginalized-Related Diminished Return (MDR) theory, for example, the protective effect of high educational attainment on mental and physical health shows a weaker protective effect for racial minority groups, particularly Black people compared to White individuals., Objectives: This longitudinal study used data of middle-aged and older adults with AD with two aims: first, to test the association between educational attainment and memory, and second, to explore racial differences in this association in the USA., Methods: Data came from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The total sample was 1673 American middle-aged and older adults. The independent variable was educational attainment measured as years of education. The main outcome was memory operationalized as Rey Auditory Verbal Learning Test (RAVLT) Verbal Forgetting percentage (VF%). Age, gender, and follow-up duration were covariates. Race was the effect modifier. Linear regression model was utilized to analyze the data., Results: Of all participants, 68 (4.1%) were Black, and the remaining were White, with a mean age of 75 years old. In the pooled sample, educational attainment did not show a significant association with memory, independent of confounders. Educational attainment showed a significant interaction with race on memory, with higher educational attainment having a different effect on memory in White patients compared to Black patients., Conclusion: The effect of higher educational attainment on memory differs for Black patients with AD compared to White patients. To prevent cognitive disparities by race, we need to go beyond racial inequality in access to resources (e.g., education) and minimize diminished returns of educational attainment for racial minorities. To tackle health inequalities, social policies should not be limited to equalizing socioeconomic status but also help minority groups leverage their available resources, such as educational attainment, and secure tangible outcomes., (© 2022. W. Montague Cobb-NMA Health Institute.)

Background: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort., Methods: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I 2 ., Findings: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I 2 =77%), 60% (56-64; I 2 =35%) were women, and 80% (72-89; I 2 =98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I 2 =78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I 2 =87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I 2 =15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I 2 =12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I 2 =0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I 2 =89%), Lewy body disease (44%, 25-62; I 2 =77%), and cerebrovascular injury (42%, 24-60; I 2 =88%)., Interpretation: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity., Funding: None., Competing Interests: Declaration of interests MC received research support from the Fonds de Recherche du Québec–Santé (FRQS). MF, FA, EC, FC, and GM receive research support from the Foundation Research on Alzheimer Disease and Italian Ministry of Healthy (#GR-2010-2303035). MEM receives research support from the NIH (R01 AG054449, R01 AG075802, U01-AG057195 and P30 AG062677). Data from Mayo Clinic (Jacksonville) was supported by the State of Florida Alzheimer's Disease Initiative and the Mayo Clinic Alzheimer's Disease Research Center. BD receives research funding from NIA R21-AG051987, P50-AG005134, and R01-DC014296 and philanthropic funding to the MGH FTD Unit including the Mooney Family Fund. KY is an Etherington posterior cortical atrophy Senior Research Fellow and is funded by the Alzheimer's Society, grant number 453 (AS-JF-18-003). The work was also supported by an Alzheimer's Research UK Senior Research Fellowship and ESRC/NIHR (ES/L001810/1) grant to SC. JMS acknowledges the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre, ARUK (ARUK-PG2017–1946), Weston Brain Institute (UB170045), Medical Research Council, and British Heart Foundation. TL is supported by an Alzheimer's Research UK senior fellowship. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the Medical Research Council. The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was also supported by the NIHR Queen Square Dementia Biomedical Research Unit, and the NIHR UCL/H Biomedical Research Centre. This work was supported by the MRC Dementia Platform UK and the UK Dementia Research Institute at UCL, which receives its funding from UK DRI, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. DG, AH, and GL receive research support from Shiley-Marcos ADRC P30 AG062429. KJ, JW, and JGR receive research funding from the NIH (R01-AG50603). BDCB receives funding from Alzheimer Nederland (#WE.15-2019-13, WE.03-2021-15, and #WE.06-2023-01). MM, JR, and KA were supported by the NIHR Cambridge Biomedical Research Centre including the Cambridge Brain Bank (BRC-1215-20014. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care) and the Race Against Dementia. M.F.M. receives research support from the NIA (1RF1AG050967). RM is supported by France Alzheimer, Fondation Recherche Alzheimer, Philippe Chatrier Foundation and by Rosita Gomez Association. OH has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche and has received consultancy or speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens. Work at the Lund University was supported by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015·0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314), and the Swedish federal Government under the ALF agreement (2018-Projekt0279). PN is supported by The Mater Foundation. DP, SPC, and GT are supported by The Italian Ministry of Health (Ricerca Finalizzata Progetto Reti Nazionale AD NET-2011-02346784). OP, NC, JB, JH, and DF were supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council (NHMRC) (GNT1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE11000102). OP is supported by an NHMRC Leadership Fellowship (GNT2008020). LA receives research support from Indiana Alzheimer's Disease Research Center (P30 AG010133 and LEADS (U01AG6057195). ER, SW, and MM received research support from the NIH (P30AG13854 and P30AG072977). BDCB receives funding from Alzheimer Nederland (#WE.15-2019-13, WE.03-2021-15, and #WE.06-2023-01). Data from Geneva was supported by Alzheimer's Disease Research Center (ADRC) grants (NIA P50 AG005138 and P30 AG066514). Data from Xuanwu Hospital was supported by the National Natural Science Foundation of China (81971011) and Beijing Municipal Science and Technology Committee (7202060). Research of Alzheimer Center Amsterdam has been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. Data from Penn Frontotemporal Degeneration Center was funded by NIH grants (R01-AG054519 and K01-AG061277). Data from MASS's group comes from The Sant Pau Initiative on Neurodegeneration cohort. LTG receives research support from the NIH (K24053435) and R01AG075802. GDR receives research support from the NIH/NIA (R35 AG072362, P30-AG062422, U01-AG057195, and P01-AG019724). Other support to GDR includes National Institute of Neurological Disorders and Stroke, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Shanendoah Foundation, Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech. LA has received personal compensation for serving as a consultant for Biogen, Two Labs, FL Dept Health, Genentech, NIH Biobank, Eli Lilly, GE Healthcare, Eisai, and Roche Diagnostics and for serving on a Data Safety and Monitoring Board for IQVIA. LA receives research support from the National Institute on Aging, the Alzheimer's Association, Roche Diagnostics, AVID radiopharmaceuticals, Life Molecular Imaging, and Eli Lilly. MFM is the section editor for Behavioral Neurology for UpToDate. JGR serves on the Drug Safety Monitoring Board for the National Institute of Neurological Disorders and Stroke StrokeNET. KAJ is an Associate Editor for Annals of Clinical and Translational Neurology and is on the editorial boards of Journal of Neurology, Acta Neuropathologica, and Neuropathology and Applied Neurobiology. JLW is an Associate Editor for Brain Connectivity and Journal of Alzheimer's Disease. RO has received research support from Avid Radiopharmaceuticals, has given lectures in symposia sponsored by GE Healthcare and is an editorial board member of Alzheimer's Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. FA is Associate Editor of NeuroImage: Clinical, has received speaker honoraria from Biogen Idec, Italfarmaco, Roche and Zambon, and receives or has received research supports from the Italian Ministry of Health, the Italian Ministry of University and Research, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council and Foundation Research on Alzheimer Disease. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla. GDR has served on Scientific Advisory Boards for Alector, Eli Lilly, Genentech, Merck, and Roche. He serves on a Data Safety and Monitoring Board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD)., Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated., Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure., Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses., Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants., (© 2023 the Alzheimer's Association.)

Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)., Methods: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70)., Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD., Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point., Methods: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70])., Results: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures., Conclusions: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant., Highlights: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present., (© 2023 the Alzheimer's Association.)

Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD)., Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden., Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers., Discussion: The effects of sex and APOE ε4 must be considered when studying these populations., Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study., Methods: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden., Results: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group., Discussion: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD., Highlights: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions., (© 2023 the Alzheimer's Association.)

Background: Logopenic variant primary progressive aphasia (lvPPA), which is most commonly an early onset variant of Alzheimer's disease (AD), is a progressive impairment in word retrieval and language expression. Clinicians often misdiagnose these patients when they present with severely unintelligible speech consistent with jargonaphasia., Methods: We reviewed all patients presenting to a behavioral neurology program over a 23-year period who met criteria for lvPPA after completion of an evaluation extending to positron emission tomography (PET) of the brain. Among these lvPPA patients, we additionally identified and characterized those whose presentation involved incomprehensible yet fluent verbal output., Results: Out of 95 patients with lvPPA, 9 (9.47%) had jargonaphasia on presentation. These patients differed from the remaining 86 patients in lacking awareness or concern for their impaired communication, having worse mental status scale scores, greater auditory comprehension difficulty, and more bilateral temporo-parietal hypometabolism. In addition, 44.4% of those with jargonaphasia, compared to 14% of those without, were bi/multilingual., Conclusion: Nearly 1 in 10 patients with lvPPA present with severely unintelligible speech. These patients have disease extending to bilateral temporoparietal areas affecting language comprehension and disease awareness. Jargonaphasia can be a confusing presentation of AD and must be differentiated from other progressive aphasias, Wernicke's aphasia, and the word salad of "schizoaphasia"., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Objective: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers., Methods: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles., Results: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline., Interpretation: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The last 2 decades have seen an explosion of neuroscience research on morality, with significant implications for brain disease. Many studies have proposed a neuromorality based on intuitive sentiments or emotions aimed at maintaining collaborative social groups. These moral emotions are normative, deontological, and action based, with a rapid evaluation of intentionality. The neuromoral circuitry interacts with the basic mechanisms of socioemotional cognition, including social perception, behavioral control, theory of mind, and social emotions such as empathy. Moral transgressions may result from primary disorders of moral intuitions, or they may be secondary moral impairments from disturbances in these other socioemotional cognitive mechanisms. The proposed neuromoral system for moral intuitions has its major hub in the ventromedial prefrontal cortex and engages other frontal regions as well as the anterior insulae, anterior temporal lobe structures, and right temporoparietal junction and adjacent posterior superior temporal sulcus. Brain diseases that affect these regions, such as behavioral variant frontotemporal dementia, may result in primary disturbances of moral behavior, including criminal behavior. Individuals with focal brain tumors and other lesions in the right temporal and medial frontal regions have committed moral violations. These transgressions can have social and legal consequences for the individuals and require increased awareness of neuromoral disturbances among such individuals with brain diseases., Competing Interests: The author declares no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The responsibility of persons with brain disorders who commit offenses may depend on how their disorders alter brain mechanisms for culpability. Criminal behavior can result from brain disorders that alter social cognition including a neuromoral system of intuitive moral emotions that are absolute (deontological) normative codes and that includes an emotion-mediated evaluation of intentionality. This neuromoral system has its hub in the ventromedial prefrontal cortex (VMPFC) with other frontal, anterior temporal-amygdalar, insular, and right temporoparietal connections. Among brain disorders, investigators report offenses in persons with brain tumors, epilepsy, and traumatic brain injury, but it is those with a form of dementia with VMPFC pathology, behavioral variant frontotemporal dementia (bvFTD), who are most prone to criminal behavior. This review presents four new patients with bvFTD who were interviewed after committing offenses. These patients knew the nature of their acts and the wrongness of the type of action but lacked substantial capacity to experience the criminality of their conduct at the intuitive, deontological, moral emotional level. Disease in VMPFC and its amygdalar connections may impair moral emotions in these patients. These findings recommend evaluation for the experience of moral emotions and VMPFC-amygdala dysfunction among persons with antisocial behavior, with or without brain disease., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Ltd.)

Background: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD)., Methods: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers ( MAPT, C9orf72, GRN ) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL)., Results: We studied 394 participants (non-carriers=143, C9orf72 =117, GRN =62, MAPT =72). In MAPT , higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR 2 =0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007)., Conclusions: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches., Competing Interests: Competing interests: JCR and JCM report being site PIs for clinical trials sponsored by Eli Lilly and Eisai. BA (Appleby) receives research support from the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), Ionis, Alector and the CJD Foundation; he has provided consultation to Acadia, Ionis and Sangamo. BCD is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda and Wave Lifesciences; receives royalties from Cambridge University Press, Elsevier and Oxford University Press; and receives grant funding from the NIA, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the Bluefield Foundation. NG has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) and the A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial; she receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. IL reports funding support from the National Institutes of Health, the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio and United Biopharma SRL – UCB; she is a Scientific advisor for Amydis and Rossy Center for Progressive Supranuclear Palsy University of Toronto . She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. AB reports research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association; he has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding and Wave and received research support from Biogen, Eisai and Regeneron. BFB has served as an investigator for clinical trials sponsored by EIP Pharma, Alector and Biogen; he receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium; he receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. AS reports research support from the NIA/NIH, the Bluefield Project to Cure FTD and the Larry L. Hillblom Foundation; he has provided consultation to Passage Bio and Takeda. PL is a site primary investigator for clinical trials by Alector, AbbVie and Woolsey; he serves as an advisor for Retrotrope; he receives research and salary support from the NIH-NIA and the Alzheimer’s Association-Part the Cloud partnership. KBC reports research support from NIH. LV reports research support from the Alzheimer’s Association, the American Academy of Neurology, the American Brain Foundation and the NIH and has provided consultation for Retrotope. KPR reports research support from the NIH and the National Science Foundation and serves on a medical advisory board for Eli Lilly. MCT has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals and Janssen; she receives research support from the Canadian Institutes of Health Research. KD-R. receives research support from the NIH and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. J. Kornak has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., case numbers 1:14-cv00121 and 1:14-cv-00686 (D. Del. filed 31 January 2014 and 30 May 2014 regarding the drug Memantine) and for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., case number 1:15-cv-975 (D. Del. filed 26 October 2015 regarding the drug Fingolimod); he has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, Inc., et al. 2018 regarding the drug Neratinib; he receives research support from the NIH. WK reports research funding from AstraZeneca, Biogen, Roche, the Department of Defense and the NIH. LF reports research funding from NIH. HJR reports research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals and receives research support from the NIH. JHK reports research support from NIH and receives royalties from Pearson Inc., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The author reports no financial relationships with commercial interests.

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp)., Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [ N  = 101]; prodromal: 0.5 [ N  = 49]; symptomatic ≥1 [ N  = 51]; not measured [ N  = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys., Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests., Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research., Highlights: The ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses., Competing Interests: Appleby, BS – receives research support from CDC, NIH, Ionis, Alector, and the CJD Foundation. He has provided consultation to Acadia, Ionis, and Sangamo.Boeve, BF – has served as an investigator for clinical trials sponsored by Alector, Biogen and Transposon. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation.Boxer, AL – receives research support from NIH (U19AG063911, R01AG038791, R01AG073482), the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave, and received research support from Biogen, Eisai, and Regeneron. As a co‐inventor of ALLFTD‐mApp tasks, Dr. Boxer has received licensing fees.Brushaber, D – nothing to disclose.Clark, AL – nothing to disclose.Dickerson, BC – Dr Dickerson is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda, Wave Lifesciences. Dr Dickerson receives royalties from Cambridge University Press, Elsevier, Oxford University Press. Dr Dickerson receives grant funding from the NIA, NINDS, NIMH, and the Bluefield Foundation.Domoto‐Reilly, K – receives research support from NIH, and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute.Fields, JA – receives research support from NIH.Forsberg, L – receives research support from NIH.Ghoshal, N – has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH.Gorno‐Tempini, ML – receives research support from NIH. As a co‐inventor of one of the ALLFTD mApp tasks, Dr Gorno‐Tempini's lab receives licensing fees , consistent with UCSF institutional policy.Graff‐Radford, N – receives royalties from UpToDate, has participated in multicenter therapy studies by sponsored by Biogen, TauRx, AbbVie, Novartis, and Lilly. He receives research support from NIH.Grossman, M – receives grant support from NIH, Avid, and Piramal; participates in clinical trials sponsored by Biogen, TauRx, and Alector; serves as a consultant to Bracco and UCB; and serves on the Editorial Board of Neurology.Hall, MGH – nothing to disclose.Heuer, HW – nothing to disclose.Huey, ED – receives research support from NIH.Irwin, D – receives support from NIH, Brightfocus Foundation, and Penn Institute on Aging.Kornak, J – has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14‐cv‐00121 and 1:14‐cv‐00686 (D. Del. filed Jan. 31, 2014, and May 30, 2014) regarding the drug Memantine; for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15‐cv‐975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod. He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, INC., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH.Kramer, J – receives research support from NIH and royalties from Pearson Inc.Kremers, W—receives research funding from AstraZeneca, Biogen, Roche, DOD, and NIH.Lapid, MI – receives research support from the NIH.Litvan, I – receives research support from the National Institutes of Health grants: 2R01AG038791‐06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911‐1 and 1R21NS114764‐01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP‐Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL‐UCB. She is a Scientific advisor for Amydis (Gratis) and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology.Mackenzie, IR – receives research funding from Canadian Institutes of Health Research, Alzheimer's Association US, NIH, Weston Brain Institute.Manoochehri, M – nothing to disclose.Masdeu, JC – is a consultant and received research funding from Eli Lilly, parent co. of Avid Radiopharmaceuticals, manufacturer of 18F‐flortaucipir, receives personal fees from GE Healthcare, grants and personal fees from Eli Lilly, grants from Acadia, Avanir, Biogen, Eisai, Janssen, NIH, Novartis, with no relation to the submitted work.Mendez, MF – receives research support from NIH.Mester, C – nothing to disclose.Nevler, N – receives research funding from the NIH and Department of Defense.Onyike, C – receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector Inc., and Transposon, Inc. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young‐Onset Dementias, and the gift from Joseph Trovato. He is a consultant with Alector, Inc. and Acadia Pharmaceuticals.Pascual, B – receives research support from NIH.Pressman, PS – receives research support from NIH.Rankin, KP – receives research support from NIH and NSF, and serves on a Medical Advisory Board for Eli Lilly.Rao, M – nothing to disclose.Rojas, JC – receives research support from NIH and is a site PI for clinical trials sponsored by Eli‐Lilly and Eisai.Rosen, HJ – has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH.Ratnasiri, B – nothing to disclose.Staffaroni, AM – received research support from the NIA/NIH, Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Dr Staffaroni is a co‐inventor of four ALLFTD mApp tasks and receives licensing fees, consistent with UCSF institutional policy.Tartaglia, M – has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, and Roche / Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen. She receives research support from Canadian Institutes of Health Research. Author disclosures are available in the supporting information.Taylor, JC – nothing to disclose.Wise, AB – nothing to disclose.Welch, AE – nothing to disclose.Wong, B – receives research support from the NIH., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The differentiation of semantic variant primary progressive aphasia from dementia and Alzheimer's disease can be difficult, particularly when the semantic anomia is pronounced. This report describes a patient who presented with complaints of memory loss and proved to have prominent semantic loss of all types of nouns, common and proper, concrete and abstract, yet continued to live independently and maintain his activities of daily living. The evaluation was consistent for semantic variant primary progressive aphasia with degradation of semantic knowledge and focal anterior temporal atrophy and hypometabolism. This report summarizes the literature and discusses the differential diagnosis of this disorder from Alzheimer's disease and related dementias., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

The dehumanization of others is a major scourge of mankind; however, despite its significance, physicians have little understanding of the neurobiological mechanisms for this behavior. We can learn much about dehumanization from its brain-behavior localization and its manifestations in people with brain disorders. Dehumanization as an act of denying to others human qualities includes two major forms. Animalistic dehumanization (also called infrahumanization) results from increased inhibition of prepotent tendencies for emotional feelings and empathy for others. The mechanism may be increased activity in the inferior frontal gyrus. In contrast, mechanistic dehumanization results from a loss of perception of basic human nature and decreased mind-attribution. The mechanism may be hypofunction of a mentalization network centered in the ventromedial prefrontal cortex and adjacent subgenual anterior cingulate cortex. Whereas developmental factors may promote animalistic dehumanization, brain disorders, such as frontotemporal dementia, primarily promote mechanistic dehumanization. The consideration of these two processes as distinct, with different neurobiological origins, could help guide efforts to mitigate expression of this behavior., Competing Interests: The author declares no conflicts of interest.

Alzheimer's disease (AD) is an age-related neurocognitive disorder that is epidemic in the elderly population. Currently, there are limited pharmacological interventions, and this has heightened the urgency to identify potential preventable or modifiable risk factors that promote resilience to the neuropathological effects of AD. The regular use of two or more languages is one such factor that may increases cognitive reserve through the long-standing executive control involved in managing multiple languages in the brain. There is also evidence that bilingualism is associated with increased brain reserve or maintenance, particularly in frontal-executive structures and networks. This review examines the current, sometimes conflicting literature on bi/multilingualism and AD. These studies have confounding variations in the assessment of age of second language onset, language proficiency, language usage, and whether determining incidence of AD or age of symptom onset. Despite these limitations, most publications support the presence of increased frontal-executive reserve that compensates for the development of AD neuropathology and, thereby, delays the emergence of clinical symptoms of dementia by about 4-5 years. Although regularly speaking more than one language does not protect against AD neuropathology, the delay in its clinical expression has a potentially significant impact on the lifelong morbidity from this age-related disease. Learning other languages may be an important modifiable factor for delaying the clinical expression of AD in later life.

Background: Veterans face specific risk factors for neurocognitive disorders. Providing them with comprehensive care for dementia and related neurocognitive disorders is a challenge as the population ages. There is a need for family-centered interventions, specialized expertise, and collaboration among clinicians and caregivers. The literature suggests that application of a transdisciplinary care model can address these needs and provide effective dementia care., Observations: The Veterans Affairs Greater Los Angeles Healthcare System has employed existing expertise to create a conference-centered transdisciplinary model that responds to the US Department of Veterans Affairs directive for a dementia system of care. This model involves direct participation of behavioral neurology, geriatric psychiatry, geriatrics, neuropsychology, nursing, and social work. In this model, the social worker serves as a dementia care manager and, along with the nurse specialist, assures long-term management through follow-up and monitoring. Transdisciplinary interactions occur in a clinical case conference where each discipline contributes to the veteran's care. The team generates a final report on treating these veterans, the caregiver's needs, referral for psychosocial services, and plans for monitoring and follow-up., Conclusions: This model could be a template of a program for implementing the Dementia System of Care across Veteran Affairs medical centers., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2023 Frontline Medical Communications Inc., Parsippany, NJ, USA.)