Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation 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 is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier 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 mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

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

Association of COVID-19 Intensity With Burnout and Perceptions of Residency Preparedness Among Medical Students.

This cross-sectional study of US medical students assesses the association of COVID-19 intensity in the clinical learning environment with student burnout and perceptions regarding residency preparedness.

US Medical Student Plans to Practice in Underserved Areas.

This study explores US medical students' intent to practice in underserved areas, analyzed by demographic characteristics.

Skin Cancer in Non-White Solid Organ Transplant Recipients: Mayo Clinic Experience.

OBJECTIVE: Solid organ transplant recipients (SOTRs) have an increased risk of skin cancer development, but limited data exist on the development pattern of cutaneous malignancies in non-White SOTRs. The aim of this study was to describe the characteristics and outcomes of non-White patients who developed skin cancer following solid organ transplantation. METHODS: We conducted a retrospective chart review of non-White SOTRs at the Mayo Clinic who underwent transplantation between November 1987 and April 2020 and subsequently developed skin cancer. RESULTS: We identified 32 non-White SOTRs who developed skin cancer in the posttransplant period. Among these, 46.9% were Hispanic/Latinx, 25% were American Indian/Alaskan Native, 21.9% were Asian, and 6.3% were Black/African American. Four patients had a history of nonmelanoma skin cancer pretransplant. In regard to skin cancer type, 21 (65.6%) patients developed squamous cell carcinoma, 15 (46.9%) developed basal cell carcinoma, 5 (15.6%) developed melanoma, and 2 (6.3%) developed sebaceous carcinoma. The median time from transplant to first posttransplant skin cancer was 7.8 years. CONCLUSIONS: Our study provides further characterization of the development of skin cancer in non-White SOTRs following transplant and identifies a variety of relevant pre- and posttransplant factors. Despite a long follow-up period, the number of patients identified remained low, which is consistent with the literature, indicating a low incidence of skin cancer development in non-White SOTRs. Continued investigation may allow for a more precise identification of risk factors and their degree of significance.

Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes. METHODS: We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test. RESULTS: We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants. DISCUSSION: We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders. TRIAL REGISTRATION INFORMATION: NCT02365922, NCT02372773, and NCT04363684.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

Dynamic stabilization home exercise program for treatment of thumb carpometacarpal osteoarthritis: A prospective randomized control trial.

STUDY DESIGN: Randomized control trial. INTRODUCTION: Thumb carpometacarpal (CMC) osteoarthritis (OA) is a common cause of hand pain and disability. Standard conservative therapy (SCT) for thumb CMC OA includes an orthosis and instruction in joint protection, adaptive equipment, and pain relieving modalities. The dynamic stability home exercise (HE) program is complementary conservative therapy designed to strengthen the stabilizing muscles of the thumb CMC. PURPOSE OF THE STUDY: To investigate whether the addition of HE to SCT (SCT+HE) was more effective at reducing pain and disability in thumb CMC OA compared to SCT alone. METHODS: The study compared 2 groups: SCT and SCT+HE. The SCT group received SCT with in-home pain management instructions, joint protection strategies with adaptive equipment, and a hand-based thumb-spica orthosis. The SCT+HE group received HE program instructions for adductor stretching and opponens and first dorsal interosseous strengthening in addition to SCT. Our primary outcome measure was the numerical rating scale (NRS) with secondary outcome measures of QuickDASH (shortened Disabilities of the Arm, Shoulder and Hand questionnaire), range of motion, grip strength, and pinch strength. Outcome measurements were assessed at first visit, 6 weeks, and 6 months. RESULTS: There was no statistical difference between the 2 groups for NRS and QuickDASH at 6 weeks (P = .28 and P = .36, respectively) or 6 months (P = .52 and P = .97, respectively). However, there was a statistically significant decrease in NRS and QuickDASH scores at 6 weeks and 6 months within both groups. CONCLUSIONS: Both SCT and SCT+HE are effective at reducing pain and disability in OA of the thumb CMC joint. Neither therapy program was superior to the other at improving NRS or QuickDASH scores at 6-week or 6-month follow-up.

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders.

INTRODUCTION: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. METHODS: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. RESULTS: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. DISCUSSION: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

A Retrospective Analysis of Gender-Based Difference in Adherence to Influenza Vaccination during the 2018-2019 Season.

INTRODUCTION: Improving flu vaccination rates in the general population is an important and effective strategy toward reducing morbidity, mortality, and the cost of seasonal influenza. In order to optimize immunization strategies, factors associated with decreased vaccination rates need to be explored. The literature suggests that there is a gender difference in the rate of influenza vaccination but is limited to population-based survey studies and also is inconsistent as to which gender has a higher rate of vaccination. The purpose of this study was to evaluate for a gender-based difference in the rate of influenza vaccination among patients who presented for an annual physical examination during the 2018 to 2019 influenza season. METHODS: In this multi-site, retrospective chart review, a total of 1193 patients (608 female and 585 male) who underwent an annual physical examination in April of 2019 were included. Baseline medical information was collected, as well as demographic characteristics and influenza vaccination status. The proportion of patients who underwent influenza vaccination was compared between males and females using multivariable logistic regression models; odds ratios (ORs) were estimated. RESULTS: The likelihood of influenza vaccination was significantly higher in females (62.8%) compared to males (53.2%) in both unadjusted analysis (OR = 1.49, P < .001) and in multivariable analysis adjusting for the potential confounding influences of clinic location, BMI, insurance type, and occupation (OR = 1.42, P = .005). Interestingly, a higher influenza vaccination rate for females compared to males was observed in patients age<60 years (OR = 1.70, P = .025) and between ages 60 and 75 (OR = 1.66, P = .009), but not for patients older than 75 years (OR = 1.12, P = .66). CONCLUSION: Our findings indicate that the rate of influenza vaccination is higher for females than for males who presented for an annual preventive physical exam and who are younger than 75 years old.

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort.

OBJECTIVE: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other. METHODS: Individuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated. RESULTS: The cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001). CONCLUSION: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

Association of uterine dimensions and route of contained morcellation following laparoscopic hysterectomy.

BACKGROUND: The aim of this study was to determine if uterine dimensions on preoperative imaging are associated with route of contained morcellation during laparoscopic hysterectomy. METHODS: This is a prospective cohort study of patients undergoing laparoscopic hysterectomy and requiring morcellation for specimen extraction from March 2017 through August 2019. A contained extraction system was inserted and manual morcellation was performed vaginally, abdominally, or via a combination of both methods in cases of failed vaginal extraction. RESULTS: A total of 47 patients were treated. Median age was 47 (range 38-70). Morcellation was performed vaginally for 29 patients (61.7%), abdominally for 13 patients (27.7%), and via combined approach for 5 patients (10.6%). The combined group had the highest frequency of patients who were black (vaginal: 24%, abdominal: 31%, combined: 100%; P=0.005), the longest median total operating time (vaginal: 167 minutes, abdominal: 183 minutes, combined: 268 minutes; P=0.006) and the longest median time of uterine morcellation (vaginal: 14 minutes, abdominal: 37 minutes, combined: 85 minutes; P<0.001). There was strong evidence of a positive correlation with time of uterine morcellation for both largest uterine diameter (Spearman's r: 0.62, P<0.001) and uterine volume (Spearman's r: 0.70, P<0.001). These associations remained consistent after multivariable linear regression models that were adjusted for route of morcellation, hysterectomy type, and BMI (both P<0.001). CONCLUSIONS: Larger uterine dimensions are associated with increased total operating and morcellation times. Uterine size and volume on preoperative imaging were not associated with route of morcellation, but there was a trend towards failed vaginal extraction when uterine dimensions exceeded 16 centimeters.

A Retrospective Analysis of Gender-Based Difference in Adherence to Initial Colon Cancer Screening Recommendations.

Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related death in the United States, despite being largely preventable and treatable. Improving overall screening rates among both men and women is considered an important and effective strategy toward reducing morbidity and mortality from CRC. In order to optimize screening strategies, factors associated with decreased compliance need to be understood. This study aimed to compare initial CRC screening rates between males and females in a population of patients who presented for an annual physical examination. Methods: A retrospective chart review study of 380 patients designed to compare rates of initial CRC screening between males and females was conducted. Patients who were seen at our institution for an annual physical examination and were between 51 and 60 years of age were included. Results: There was no evidence of a difference in the rate of initial colon cancer screening between females (83.0%) and males (80.9%) in either unadjusted analysis (odds ratio = 1.16, P = .59) or in multivariable analysis adjusting for potential confounding variables (odds ratio = 1.16, P = .61). Conclusions: There was no significant difference in the rate of initial CRC screening between males and females who presented for an annual physical examination. This suggests that designing interventions to improve screening specific to gender may not be needed in a population of patients who attend routine preventive health examinations. Further study is needed in the general population to examine for gender-based differences in initial CRC screening among patients who do not regularly follow up for preventive examinations.

Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.

OBJECTIVE: To investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: We investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy. RESULTS: RSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11). CONCLUSIONS: The RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

Association of Tripartite Motif Containing 11 rs564309 With Tau Pathology in Progressive Supranuclear Palsy.

BACKGROUND: Intronic variant rs564309 in tripartite motif containing 11 (TRIM11) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP-Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes. OBJECTIVE: Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi-quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies. METHODS: 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309-A using multivariable linear regression models. RESULTS: TRIM11 rs564309-A was associated with increased neurofibrillary tangles pathology (P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores. CONCLUSIONS: TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society.

Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study.

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.