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Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve

Abstract Introduction Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity in Alzheimer's disease, but its role in the behavioral variant of frontotemporal dementia (bvFTD) is unknown. Methods We included 216 patients with bvFTD and 235 controls with magnetic resonance imaging (MRI) from a large multicenter cohort. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We followed the residuals approach to study behavioral and cognitive reserve. Results At diagnosis, women with bvFTD showed greater atrophy burden in the frontotemporal regions compared to men despite similar clinical characteristics. For a similar amount of atrophy, women demonstrated better‐than‐expected scores on executive function and fewer changes in apathy, sleep, and appetite than men. Discussion Our findings suggest that women might have greater behavioral and executive reserve than men, and neurodegeneration must be more severe in women to produce symptoms similar in severity to those in men.


BACKGROUND
The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive personality and behavioral change along with social, cognitive, and functional deterioration. 1,2 This syndrome is the most frequent presentation of frontotemporal lobar degeneration (FTLD). In contrast with typical Alzheimert's disease (AD), patients with bvFTD show an anterior pattern of neurodegeneration with selective involvement of the frontotemporal cortex. [2][3][4] These structures are critical nodes for the sustainment of executive function, language, and social cognition.
Structural imaging biomarkers, such as magnetic resonance imaging (MRI), are powerful tools for the in vivo study of neurodegenerative diseases. The identification of frontotemporal atrophy on MRI can increase diagnostic certainty of underlying FTLD in bvFTD, but patterns of atrophy and progression are heterogeneous. 5,6 The observed variability in the patterns of atrophy, together with variable clinical presentation and rates of longitudinal decline, hampers accurate predictions of treatment effects using clinical or imaging outcome measures. 7 A better understanding of the factors determining clinical and structural heterogeneity is an essential step for the development of precision medicine approaches in neurodegenerative dementias. 8,9 Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity at the single-subject level, and the importance of sex-related differences has been recently highlighted as a research priority in the study of neurodegenerative dementias. 8,[10][11][12][13] To date, most studies investigating sex differences in neurodegenerative dementias have focused on AD. 14 However, some studies in FTLD syndromes indicate that sex could influence clinical presentation and diagnosis. 8,[15][16][17][18][19] For instance, in large cohorts of FTLD, patients presenting with bvFTD included a higher proportion of men, whereas patients presenting the non-fluent variant of primary progressive aphasia had a higher proportion of women (72% and 28% of men, respectively, in the largest pathology proven cohorts). 3,20 Under normal conditions, sex-related differences in brain structure have been reported consistently in the frontotemporal cortex with higher cortical thickness in women. 21,22 Moreover, the observed difference in the ability to cope with pathology and sustain cognitive function (known as cognitive reserve) can also be modulated by sex. 19,23 In this multicenter study, we aimed to characterize the impact of sex on clinical presentation, longitudinal decline, and cortical thickness in bvFTD. We further explored the existence of sex differences in cognitive reserve by following the residuals approach to operationalize reserve as having better cognition and fewer behavioral changes than predicted by cortical thickness (a proxy of pathology). To do this, we modeled the relationship between cognition or behavior with cortical thickness and used each individual's residual as a proxy of their reserve. 19,24 We anticipated three possible scenarios: (1) men and women with bvFTD may show similar clinical presentation, progression, and burden of frontotemporal atrophy; (2)

Study population
Participants with bvFTD were recruited from two cohorts, at three dif-

Measures of cognitive function
The Mini-Mental State Examination (MMSE) was recorded in all centers as a general measure of cognitive impairment. 31 The MMSE was also recorded during follow-up. Detailed cognitive functioning was assessed using two previously published neuropsychological protocols. 2, 28 We selected cognitive measures from each protocol measuring parallel neuropsychological constructs, and we defined four main neuropsychological domains (memory, executive functioning, language, and visuospatial functioning) as in previous multicenter studies. 32

Behavioral measures
We recorded the specific features of bvFTD diagnostic criteria present at diagnosis. We selected the frequency-by-severity product of the Neuropsychiatric Inventory (NPI) and the total score of the NPI (sum of the frequency-by-severity scores) as measures of behavioral changes independent of diagnostic criteria recorded in all centers. 34 Because the frequency-by-severity product of the NPI could be influenced by the characteristics of the informant (gender, values, and so on) we also considered the count of abnormal behaviors (herein, NPI behavior count) as a measure of behavioral burden less dependent on the informants' characteristics. Finally, we included the Geriatric Depression Scale (GDS) to quantify symptoms of depression at baseline. 35

Progression and survival analyses
We used linear mixed-effects analyses controlling for age, sex, base-

MRI acquisition
The images were acquired on scanners from seven different manufacturers using different imaging protocols (Table S1)

MRI processing
MRIs were processed with the CAT12 toolbox within SPM12 (running in MATLAB r2019b). 39,40 It is notable that we performed cortical thickness analyses instead of volume methods, because the cortical thickness is not significantly affected by total intracranial volume, a measure that is known to differ between men and women (Supplementary Methods). 41 We obtained total intracranial volume and white matter hyperintensities volumes, as implemented in CAT12. Finally, we calculated the mean frontotemporal cortical thickness by averaging the mean cortical thickness of all the frontal and temporal regions in the Desikan atlas.

Group comparison of cortical thickness
We performed separate group-comparisons analyses in men and women following the recommendation for the study of sex-related differences in neurodegenerative dementias. 8

Interaction between group and sex
In a separate multiple regression model, we tested sex x group (bvFTD vs healthy control) interaction on cortical thickness in all the participants (Supplementary Methods and Figure S1).

Cognitive and behavioral reserve analyses
Next, we investigated the existence of sex differences in cognitive and behavioral reserve by following the residuals approach. 19,24 First, we fitted different linear regression models with each of the cognitive zscores and NPI scores as the response variable and age, education, and frontotemporal cortical thickness as predictors. This model provided an individual's predicted cognition/behavior scores for a certain level of atrophy. Here, we operationalized "reserve" as having better function than is predicted by the cortical thickness (a proxy of pathology) and used each individual's residual as a proxy of their reserve. This procedure was done for each cognitive composite and each NPI frequency x severity scores as the response variable. Robust Welch t tests with bias-corrected accelerated bootstrapping on 1000 samples were then performed to test for a difference in residuals (ie, reserve) between women and men.

Other statistical analyses
Data were explored for normality using the Kolmogorov-Smirnov test.
Between-group differences in baseline characteristics were assessed using t test, analysis of variance (ANOVA), or Kruskal-Wallis test for continuous variables and chi-square test for categorical data. We computed the effect size (partial Eta Squares) in analysis of covariance (ANCOVA) analyses of the difference in cognitive composites between bvFTD participants and healthy controls after adjusting by age and education (Table S5). To obtain robust confidence intervals, we estimated 95% confidence intervals (95% CIs) with bootstrapping-based methods (bias-corrected and accelerated for 1000 samples). Statistical significance for all tests was set at 5% (α = .05), and all statistical tests were two sided. All analyses were performed using SPSS 25 (Armonk, NY: IBM Corp.).

RESULTS
Age at MRI and education were similar between men and women with bvFTD and between participants with bvFTD and healthy controls (Table 1). Of note, age at disease onset and measures of disease severity (CDRsb and CDR plus NACC FTLD) were similar between men and women with bvFTD (Table 1). An FTLD mutation was identified in 22% of bvFTD participants (28 C9orf72 (Table 1). Within bvFTD participants with pathology-proven FTLD, we observed a higher frequency of FTLD-Fused in Sarcoma (FTLD-TDP; Table 1). Particularly, FTLD-TDP type B was more frequent in women than in men with FTLD (Table S9).
Women and men showed a similar frequency of bvFTD diagnostic features ( Figure 2A). In addition, on average, men and women showed the same number of features of the diagnostic criteria at diagnosis (Mann-Whitney U = 3.404; P = .737). Disinhibition and delusions were more frequently reported (present vs absent) in women than in men with bvFTD (Table 1). However, we only observed higher frequency x severity scores on women in delusions ( Figure 2B). The NPI total score, the NPI behavior count, and the GDS score were similar between men and women with bvFTD (Table 1).
Next, we compared the cognitive profile between men and women with bvFTD. As expected, bvFTD participants were more impaired than age-and education-matched healthy controls in all four domains.
Detailed information on full the neuropsychologic testing for each cohort can be found in Table S3 to S4. However, no differences were noted between men and women in any cognitive domain in the bvFTD group ( Figure 2C). Of note, the MMSE scores were lower in women with bvFTD compared to men. However, the effect size of the difference was small (Table S5).
As shown in Figure 3A, disease progression over 1 year of followup was similar between men and women with bvFTD.  (Table S8).
Men with bvFTD showed reduced cortical thickness in frontotemporal structures when compared to healthy controls of the same sex ( Figure 4A). Similarly, women with bvFTD showed reduced cortical thickness in frontotemporal structures when compared to healthy controls of the same sex ( Figure 4B). However, we observed larger effect sizes than in men, as illustrated in Figure 4C. Of note, we found similar results when we performed separate analyses in each cohort ( Figure   S1). Next, we directly compared cortical thickness between men and women with bvFTD and found that women with bvFTD had reduced cortical thickness compared to men with bvFTD in several frontotemporal regions of both hemispheres ( Figure S2). It is important to note that we found a significant group (bvFTD or healthy control) by sex interaction in frontotemporal structures, indicating that, at diagnosis, women with bvFTD had lost more frontotemporal gray matter than men with bvFTD after accounting for age, education, MMSE, and MRI scan ( Figure 4D and Figure S3).
To more directly evaluate potential behavioral and cognitive reserve differences by sex, we took the residuals approach. We first fitted multiple linear regression models with NPI and cognitive z-scores as the response variables and with age, education, and cortical thickness as predictors (Table S6). For illustrative purposes, Figure 5 shows the relationship between apathy NPI score, executive z-score, and frontotemporal cortical thickness ( Figure 5A and D). The sex-comparison of the residuals obtained in these linear regression models suggests that women had lower-than-expected apathy (t(348) = 2.5, P = .012, Figure 5B) and higher-than-expected executive z-score (t(352) = −2.1, P = .039, Figure 5D) than men, given their frontotemporal atrophy.
We also observed lower-than-expected sleep and appetite change    (three with neuropathology available) and two TARDBP. ¶ The proportion of FTLD-TDP was higher in women with FTLD diagnosis than in men (82% vs 55%, P < .05, Bonferroni adjusted). For additional details on the neuropathological findings please refer to Table S9. # Difference between men and women (P < .05, Bonferroni adjusted).
**Imaging quality rating obtained from CAT12 software (percentages closer to 100% indicating a better quality of MRI).
did not observe a significant difference in the residuals for the rest of the NPI and cognitive scores (Table S7).

DISCUSSION
In this multicenter study we explored the impact of biological sex on the clinical presentation, prognosis, and cerebral structure of bvFTD, a neurodegenerative syndrome characterized by the selective vulnerability of frontal and temporal lobes. 3,4 We found that women with bvFTD showed a higher burden of frontal atrophy at diagnosis compared to men despite very subtle differences in cognitive and functional impairment, progression, and survival. Next, we followed the residuals approach to investigate sex-related differences in reserve.
We found that for a given amount of atrophy, women performed better-than-expected on executive function and displayed fewer general behavioral changes, and particularly fewer changes in apathy, sleep, and appetite than men. This observation suggests that women with bvFTD have higher behavioral and executive reserve than men.
Although previous works have reported significant sex differences in Alzheimer's disease (or AD), this is the first study investigating this important topic in bvFTD, one of the first causes of early onset dementia and the first clinical presentation of FTLD.
We found that at diagnosis, women with bvFTD had significantly more atrophy than men, both in the whole sample and when segregating participants in two cohorts. It is important to note that we first performed stratified analyses by sex as recommended in recent consensus paper for the investigation of sex differences. 8 By doing this, we avoided the potential mitigation of sex-related differences in cerebral structure when introducing sex as a covariate in structural analyses. 8 We next investigated if the observed sex differences in cortical thinning could be related to disease severity at diagnosis. Indeed, previous observations suggested that the diagnosis of bvFTD could be delayed in women because of higher misdiagnosis with psychiatric diseases compared to men. 16  For this purpose, large multicenter cohorts of both sporadic FTLD syndromes and FTLD-related mutation carriers would be of particular interest. 42,43 Despite similar diagnostic features at diagnosis, men and women displayed some subtle differences. We replicated previous observations of lower MMSE scores in women with bvFTD. 2 However, the effect size of the observed difference in MMSE scores was small (inferior to 0.2). Because the MMSE combines language, memory, and visuospatial tasks, we hypothesize that this combination may have an additive effect to unveil small differences in general cognition between men and women with bvFTD that were not statistically significant when assessing independent tests or cognitive domains. We also found that a slightly higher frequency of delusions and disinhibition in women with bvFTD. 2 However, only delusions (and not disinhibition) showed a higher frequency by severity score in women. This finding could be related to the higher frequency of FTLD-TDP in women with bvFTD in our sample. However, a recent study evidenced a higher frequency of hallucinations (and not delusions) in FTLD-TDP compared to other FTLD subtypes. 44 Moreover, a higher frequency of delusions has also been observed in women with AD. 45 Although sex may play a role in the higher frequency of delusions, more studies are needed to explore the The inclusion of a large group of age-and sex-matched healthy controls allowed us to study the specific contribution of the diagnostic group (healthy control vs bvFTD), sex, and the interaction between group and sex on frontotemporal thickness. We found a significant sex by group interaction in frontotemporal regions after accounting for the effect of age, education, MMSE, and MRI scan. This is a critical finding of the study, indicating that women have lost more cortical thickness at the moment of bvFTD diagnosis than men after accounting for potential confounding factors. These results, together with the observed null to small effect sizes in the cognitive features and longitudinal decline between men and women with bvFTD, suggested that women could better tolerate frontotemporal pathology. To further test this hypothesis, we followed the residuals approach as a proxy to investigate potential sex differences in reserve. We showed that, for a given amount of atrophy, women with bvFTD had better-than-expected scores on executive function and less than expected apathy, sleep, and appetite behavior changes. We interpret these results as indirect evidence of higher brain reserve in women. However, the concept of reserve encompasses different dynamic processes that could also play a significant role in the observed differences. 19 It should be noted that many of these processes cannot be captured with structural bral pathology and cognitive changes in AD. 23,46 Previous studies in F I G U R E 5 Women with bvFTD have higher behavioral and cognitive reserve than men. (A) Scatter plot between NPI apathy score (higher values represent more apathy) and frontotemporal cortical thickness (negative values represent higher atrophy). (B) Comparison of predicted residuals for NPI apathy score between men and women. Residuals were obtained in a general linear model with NPI apathy score as response variable and age, education, and frontotemporal cortical thickness as predictors. (C) Scatter plots between executive z-score (negative values represent worst performance) and frontotemporal cortical thickness (negative values represent higher atrophy). (D) Comparison of predicted residuals for executive z-score between men and women. Residuals were obtained in a general linear model with NPI apathy score as response variable and age, education, and frontotemporal cortical thickness as predictors. * P < .05 (Robust Welch t test with bias-corrected accelerated bootstrapping on 1000 samples). Abbreviations: bvFTD, behavioral variant of frontotemporal dementia; NPI, Neuropsychiatric Inventory AD have identified the anterior cingulum as an important region for resilience. 47 Because an anterior pattern of neurodegeneration characterizes the bvFTD syndrome, the mechanisms and structures supporting reserve in bvFTD may be different than in AD, a disease characterized by a posterior pattern of neurodegeneration.

Strengths and limitations
This study has some limitations. First, most participants in this study did not have pathological confirmation of neurodegenerative disease.
However, the diagnosis of bvFTD was made by expert clinicians based on established criteria, and participants with decreased diagnostic certainty of underlying FTLD were excluded to avoid the inclusion of participants with the so-called "phenocopy syndrome." Of note, the survival of included bvFTD participants was similar to that reported in other large studies after excluding non-neurodegenerative causes of bvFTD. 48 Second, in this study, we focused on biological sex, but more studies are needed to understand the role of gender (understood as a social construct) in the diagnosis of bvFTD and other neurodegenerative dementias. Finally, the rating of behavioral change was based on questionnaires administered to the caregiver, and it is possible that some of the informants' characteristics (including biological sex) could have meaningfully influenced the ratings. However, we also obtained significant results with the NPI behavior count, a measure that is less dependent on the subjective assessment of symptom severity. Moreover, our main results were not limited to behavioral measures, since we also found evidence for higher executive reserve in women. Future studies should examine the effect of biological sex and gender of the informant on NPI ratings and assess the impact of using clinician-based instruments (such as the NPI-clinician version). 49

CONCLUSION
We describe striking differences in frontotemporal atrophy between men and women with bvFTD despite showing less evident differences in baseline clinical characteristics and trajectories. It is notable that our results also support the existence of sex-related differences in the ability to cope with frontotemporal neurodegeneration and add to the growing evidence highlighting the importance of considering sex for the design of research studies and clinical trials in neurodegenerative dementias.

ACKNOWLEDGMENTS
The authors thank the patients and their relatives for their support for  and Roche Diagnostics and has filed a patent application of synaptic markers in neurodegenerative diseases. HJR reports no disclosures.