Highlights
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• Bilinguals with frontotemporal dementia (FTD) exhibit reduced thalamic volume.
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• Bilinguals with FTD show a similar level of cognitive functioning as monolinguals.
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• Bilingualism contributes to cognitive reserve in FTD pathology.
1. Introduction
Recent evidence suggests that modifying risk factors by using effective strategies across the lifespan may prevent or delay up to 45% of dementias through enhancing reserve/resilience (Livingston et al., Reference Livingston, Huntley, Liu, Costafreda, Selbæk, Alladi, Ames, Banerjee, Burns, Brayne, Fox, Ferri, Gitlin, Howard, Kales, Kivimäki, Larson, Nakasujja, Rockwood and Mukadam2024). Reserve/resilience is an evolving framework that intends to explain the ability of the brain to adapt and cope with neuropathology and cognitive decline (Bartrés‐Faz et al., Reference Bartrés‐Faz, Arenaza‐Urquijo, Ewers, Belleville, Chételat, Franzmeier, Gonneaud, Echevarri, Okonkwo, Schultz, Valenzuela, Stern and Vemuri2020; Stern et al., Reference Stern, Albert, Barnes, Cabeza, Pascual-Leone and Rapp2023). Brain reserve and cognitive reserve are two concepts that have been proposed under the reserve/resilience framework. Brain reserve refers to the neurobiological capital or the structural brain integrity available at a given time. Brain reserve is exhibited as increased brain structure to maintain cognitive functioning. On the other hand, cognitive reserve is the ability of the brain to uphold cognitive abilities in the presence of reduced structural integrity of the brain. This indicates that reserve/resilience can operate in multiple ways in relation to brain structure and function. Several life-course factors such as educational attainment, occupational complexity, physical activity and engaging in cognitively stimulating activities contribute to improving reserve/resilience (Grebe et al., Reference Grebe, Vonk, Galletta and Goral2024; Perneczky et al., Reference Perneczky, Kempermann, Korczyn, Matthews, Ikram, Scarmeas, Chetelat, Stern and Ewers2019).
Over the last decade, bilingualism has been demonstrated to be a promising life-course factor that could enhance reserve/resilience. Evidence for this association came initially from studies on bilingualism and age at the onset of dementia especially among persons with Alzheimer’s disease (AD) (Alladi et al., Reference Alladi, Bak, Duggirala, Surampudi, Shailaja, Shukla, Chaudhuri and Kaul2013; Anderson et al., Reference Anderson, Hawrylewicz and Grundy2020; Bialystok et al., Reference Bialystok, Craik and Freedman2007; Craik et al., Reference Craik, Bialystok and Freedman2010; Gollan et al., Reference Gollan, Salmon, Montoya and Galasko2011). The results from these studies revealed that bilingualism delayed the age at which symptoms first appear in dementia. Bilingualism being the norm in India, studies from the country extended this observation to frontotemporal dementia (FTD). Bilingualism delayed the onset of symptoms by 6 years in FTD (Alladi et al., Reference Alladi, Bak, Duggirala, Surampudi, Shailaja, Shukla, Chaudhuri and Kaul2013), an association more pronounced in behavioral variant FTD (bvFTD) than language and motor variants (Alladi et al., Reference Alladi, Bak, Shailaja, Gollahalli, Rajan, Surampudi, Hornberger, Duggirala, Chaudhuri and Kaul2017). A delay in onset was also demonstrated among bilingual speakers with a logopenic variant of primary progressive aphasia (PPA) associated typically with AD pathology (de Leon et al. Reference de Leon, Grasso, Welch, Miller, Shwe, Rabinovici, Miller, Henry and Gorno-Tempini2020). Conversely, there has been a finding that reported no delay in age at the onset of disease in a cohort of persons with FTD (de Leon et al., Reference de Leon, Grasso, Allen, Escueta, Vega, Eshghavi, Watson, Dronkers, Gorno-Tempini and Henry2024). However, other indications of cognitive reserve such as a slower rate of cognitive decline have been reported (Costumero et al., Reference Costumero, Marin-Marin, Calabria, Belloch, Escudero, Baquero, Hernandez, de Miras, Costa, Parcet and Ávila2020). These findings indicate an emerging body of evidence that bilingualism serves as a reserve/resilience variable against AD and FTD dementia subtypes, thereby requiring further exploration of the underlying neural basis.
The neural mechanisms of reserve/resilience in the context of bilingualism have been examined using grey matter volume/density, glucose metabolism, connectivity and cortical thickness. Several studies in bilingualism and healthy cognitive aging suggest higher brain reserve in bilinguals. This is demonstrated by increased grey matter of anterior cingulate cortex, inferior parietal lobe, orbitofrontal, hippocampus and left temporal pole (Abutalebi et al., Reference Abutalebi, Canini, Della Rosa, Sheung, Green and Weekes2014; Abutalebi, Canini, et al., Reference Abutalebi, Canini, Della Rosa, Green and Weekes2015; Abutalebi, Guidi, et al., Reference Abutalebi, Guidi, Borsa, Canini, Della Rosa, Parris and Weekes2015; Del Maschio et al., Reference Del Maschio, Sulpizio, Gallo, Fedeli, Weekes and Abutalebi2018; Luk et al., Reference Luk, Bialystok, Craik and Grady2011; Olsen et al., Reference Olsen, Pangelinan, Bogulski, Chakravarty, Luk, Grady and Bialystok2015; Voits, Robson, et al., Reference Voits, Robson, Rothman and Pliatsikas2022). Moreover, there is evidence of increased white matter (WM) integrity of the corpus callosum, superior longitudinal fasciculus, right inferior fronto-occipital fasciculus and uncinate fasciculus (Luk et al., Reference Luk, Bialystok, Craik and Grady2011). A few studies also indicate decreased WM and grey matter integrity in older bilinguals despite preserved cognitive performance supporting the cognitive reserve hypothesis (Gold et al., Reference Gold, Johnson and Powell2013; Stevens et al., Reference Stevens, Khan, Anderson, Grady and Bialystok2023). Bilingualism has also been consistently associated with enhanced functional connectivity (Grady et al., Reference Grady, Luk, Craik and Bialystok2015; Stevens et al., Reference Stevens, Khan, Anderson, Grady and Bialystok2023).
In neurodegenerative diseases, bilinguals typically demonstrate better cognitive reserve. Among persons with AD, bilinguals had greater atrophy of the medial temporal lobe on CT scans compared to monolinguals, despite having similar cognitive functioning (Schweizer et al., Reference Schweizer, Ware, Fischer, Craik and Bialystok2012). Literature suggests that bilinguals with AD have better preserved cognitive functioning compared to monolinguals despite having greater hypometabolism in several regions of the brain (Perani et al., Reference Perani, Farsad, Ballarini, Lubian, Malpetti, Fracchetti, Magnani, March and Abutalebi2017; Sala et al., Reference Sala, Malpetti, Farsad, Lubian, Magnani, Frasca Polara, Epiney, Abutalebi, Assal, Garibotto and Perani2022). Bilinguals also have better metabolic connectivity as a compensatory mechanism to counteract the hypometabolism. Studying brain volumes to examine the neural basis of cognitive reserve is another well-established method to investigate the effect of bilingualism on brain structure (Abutalebi, Canini, et al., Reference Abutalebi, Canini, Della Rosa, Green and Weekes2015; Abutalebi, Guidi, et al., Reference Abutalebi, Guidi, Borsa, Canini, Della Rosa, Parris and Weekes2015; Calvo et al., Reference Calvo, Anderson, Berkes, Freedman, Craik and Bialystok2023; Costumero et al., Reference Costumero, Marin-Marin, Calabria, Belloch, Escudero, Baquero, Hernandez, de Miras, Costa, Parcet and Ávila2020; Voits, Robson, et al., Reference Voits, Robson, Rothman and Pliatsikas2022). Bilingual speakers with AD were reported to have lesser grey matter density in the medial temporal regions (Duncan et al., Reference Duncan, Nikelski, Pilon, Steffener, Chertkow and Phillips2018) and higher volume in the ventral subcortical structures (Raji et al., Reference Raji, Meysami, Merrill, Porter and Mendez2020) while having similar levels of cognitive functioning compared to their monolingual counterparts. The neural atrophy in the disease-related regions in bilinguals is compensated through enhanced functional connectivity and better neural efficiency to maintain optimal cognitive functions (Grundy et al., Reference Grundy, Anderson and Bialystok2017; Marin-Marin et al., Reference Marin-Marin, Palomar-García, Miró-Padilla, Adrián-Ventura, Aguirre, Villar-Rodríguez and Costumero2021; Perani et al., Reference Perani, Farsad, Ballarini, Lubian, Malpetti, Fracchetti, Magnani, March and Abutalebi2017; Sala et al., Reference Sala, Malpetti, Farsad, Lubian, Magnani, Frasca Polara, Epiney, Abutalebi, Assal, Garibotto and Perani2022). The constant switching between two languages in bilinguals exercises and improves their executive and attentional control mechanisms (Abutalebi & Green, Reference Abutalebi and Green2007; Bialystok & Craik, Reference Bialystok and Craik2022; Green & Abutalebi, Reference Green and Abutalebi2013; Verreyt et al., Reference Verreyt, Woumans, Vandelanotte, Szmalec and Duyck2016). This in turn leads to neuroplasticity both at the structural and functional levels and protects against neurodegenerative dementias (Bialystok, Reference Bialystok2021; Grundy et al., Reference Grundy, Anderson and Bialystok2017; Pliatsikas, Reference Pliatsikas2020; Voits, DeLuca, et al., Reference Voits, DeLuca and Abutalebi2022).
In the light of these findings, several models of bilingualism have emerged to provide a comprehensive framework to understand the neural adaptations as a consequence of bilingualism. The dynamic restructuring model (DRM; Pliatsikas, Reference Pliatsikas2020) proposes that the increased grey matter in the frontotemporal regions among bilingual older adults compared to monolinguals (i.e., greater brain reserve) is the result of increased resistance to age-related decline due to increased neuronal efficiency attained during the consolidation phase of bilingual experience. The subcortical regions such as basal ganglia and thalamus have been previously shown to have significance in the realm of bilingualism (Abutalebi et al., Reference Abutalebi, Della Rosa, Gonzaga, Keim, Costa and Perani2013; Burgaleta et al., Reference Burgaleta, Sanjuán, Ventura-Campos, Sebastian-Galles and Ávila2016; DeLuca, Rothman, Bialystok, et al., Reference DeLuca, Rothman, Bialystok and Pliatsikas2019; DeLuca, Rothman, & Pliatsikas, Reference DeLuca, Rothman and Pliatsikas2019; Korenar et al., Reference Korenar, Treffers-Daller and Pliatsikas2023; Pliatsikas et al., Reference Pliatsikas, DeLuca, Moschopoulou and Saddy2017; Yee et al., Reference Yee, Yap, Korenar, Saddy and Pliatsikas2024). The bilingual adaptations of the subcortical regions are more dynamic across the lifespan (Pliatsikas, Reference Pliatsikas2020). The Bilingual Anterior to Posterior and Subcortical Shift hypothesis (Grundy et al., Reference Grundy, Anderson and Bialystok2017) suggests that there is an increased reliance on posterior and subcortical structures with increasing second language expertise. Corroborating with this, the DRM predicts that with increasing second language expertise there will be an expansion of the subcortical structures followed by contraction after attaining efficiency in bilinguals.
While the neural mechanisms of cognitive reserve in dementia have been investigated in considerable detail in AD, only a few have focused on FTD (Beyer et al., Reference Beyer, Meyer-Wilmes, Schönecker, Schnabel, Sauerbeck, Scheifele, Prix, Unterrainer, Catak, Pogarell, Palleis, Perneczky, Danek, Buerger, Bartenstein, Levin, Rominger, Ewers and Brendel2021; Borroni et al., Reference Borroni, Premi, Agosti, Alberici, Garibotto, Bellelli, Paghera, Lucchini, Giubbini, Perani and Padovani2009; Grebe et al., Reference Grebe, Vonk, Galletta and Goral2024; Premi et al., Reference Premi, Garibotto, Alberici, Paghera, Giubbini, Padovani and Borroni2012), a syndrome characterised by its unique behavioral and cognitive profile (Olney et al., Reference Olney, Spina and Miller2017). Even though FTD has been typically known for the frontal and temporal patterns of atrophy, there has been a surge in evidence suggesting insular and subcortical neurodegeneration earlier in the disease as well as in presymptomatic stages (Bocchetta et al., Reference Bocchetta, Gordon, Cardoso, Modat, Ourselin, Warren and Rohrer2018, Reference Bocchetta, Malpetti, Todd, Rowe and Rohrer2021; Planche et al., Reference Planche, Mansencal, Manjon, Tourdias, Catheline and Coupé2023; Poos et al., Reference Poos, Grandpierre, van der Ende, Panman, Papma, Seelaar, van den Berg, van ‘t Klooster, Bron, Steketee, Vernooij, Pijnenburg, Rombouts, van Swieten and Jiskoot2022; Rohrer et al., Reference Rohrer, Nicholas, Cash, Swieten, Dopper, Jiskoot, Minkelen, Rombouts, Cardoso, Clegg, Espak, Mead, Thomas, Vita, Masellis, Black, Freedman, Keren, MacIntosh and Rossor2015).
Previous studies have found that bilingualism in persons with AD attenuates the effect of brain atrophy in disease-related regions (medial temporal and temporoparietal) on cognitive functioning (Duncan et al., Reference Duncan, Nikelski, Pilon, Steffener, Chertkow and Phillips2018; Perani et al., Reference Perani, Farsad, Ballarini, Lubian, Malpetti, Fracchetti, Magnani, March and Abutalebi2017; Sala et al., Reference Sala, Malpetti, Farsad, Lubian, Magnani, Frasca Polara, Epiney, Abutalebi, Assal, Garibotto and Perani2022; Schweizer et al., Reference Schweizer, Ware, Fischer, Craik and Bialystok2012). Therefore, this study investigated the effect of bilingualism on regional volumes of frontal, temporal and subcortical regions among persons with FTD. Based on insights from previous studies and in concordance with the cognitive reserve theory, we hypothesized that bilinguals with FTD would have more severe atrophy compared to monolinguals, despite similar levels of cognitive functioning.
2. Methods
2.1. Participants
We recruited 73 persons with a diagnosis of FTD from the Cognitive Disorders Clinic in the Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India. All patients attending the clinic were assessed by experienced cognitive neurologists (S.A, S.R, F.A) and underwent a detailed clinical history, neuropsychological assessment and an magnetic resonance imaging (MRI) scan. Participants having any other major neurological or psychiatric disorders were excluded. Five participants were excluded due to motion artifacts in their T1-weighted MR images. Sixty-eight persons with FTD (42 bilinguals and 26 monolinguals) were included in the study. Fifty participants were diagnosed as bvFTD and 18 were primary progressive aphasias. The diagnoses were made using the standard criteria (Gorno-Tempini et al., Reference Gorno-Tempini, Hillis, Weintraub, Kertesz, Mendez, Cappa, Ogar, Rohrer, Black, Boeve, Manes, Dronkers, Vandenberghe, Rascovsky, Patterson, Miller, Knopman, Hodges, Mesulam and Grossman2011; Rascovsky et al., Reference Rascovsky, Hodges, Knopman, Mendez, Kramer, Neuhaus, van Swieten, Seelaar, Dopper, Onyike, Hillis, Josephs, Boeve, Kertesz, Seeley, Rankin, Johnson, Gorno-Tempini, Rosen and Miller2011). Language history, demographic detail and educational status were obtained by interviewing the patient and a reliable family member. The participants were considered as bilinguals if they met communicative demands in more than one language (Mohanty, Reference Mohanty1994). The combination of languages the participants spoke is added in Table S1, supplementary material. All participants were reported as right-handed.
The study protocol was approved by the Institutional Ethics Committee of NIMHANS and informed consent was obtained from all the participants and/or their caregivers.
2.2. Cognitive assessments
Cognition was evaluated using Addenbrooke’s Cognitive Examination (ACE)-III which is standardized across eight Indian languages (Bhattacharyya et al., Reference Bhattacharyya, Mukherjee, Mukherjee, Das, Dogra, Das and Biswas2022; Mekala et al., Reference Mekala, Paplikar, Mioshi, Kaul, Divyaraj, Coughlan, Ellajosyula, Jala, Menon, Narayanan, Narayan, Aghoram, Nehra, Rajan, Sabnis, Singh, Tripathi, Verma, Saru and Alladi2020). It evaluates five domains of cognition (attention, memory, fluency, language and visuospatial abilities) and is used as a measure of global cognitive functioning with a maximum score of 100. The assessment was conducted in the mother tongue of the participant by an examiner proficient in that language. The clinical dementia rating (CDR) scale was used to determine the severity of dementia (Morris, Reference Morris1993). A semi-structured interview was conducted with the patient and the caregiver to rate the impairment of the patient in each of the six cognitive functioning categories (memory, orientation, judgement and problem-solving, community affairs, home and hobbies and personal care). Each category was rated on a five-point scale: no impairment, very mild/questionable impairment, mild impairment, moderate impairment and severe impairment. Finally, a global CDR score was obtained indicating no dementia, very mild dementia, mild dementia, moderate dementia or severe dementia.
2.3. Propensity score matching
A significant challenge to the studies on bilingualism, brain and cognition is the effect of confounding variables (Paap et al., Reference Paap, Johnson and Sawi2016). This study used the propensity score matching (PSM) technique (Rosenbaum, Reference Rosenbaum1989), which has been previously utilized in studies investigating bilingualism and cognitive reserve (Anderson et al., Reference Anderson, Grundy, De Frutos, Barker, Grady and Bialystok2018; Berkes et al., Reference Berkes, Calvo, Anderson and Bialystok2021). This technique uses logistic regression to assign propensity score values to determine the probability of individuals being assigned to the treatment group (Austin, Reference Austin2011), thereby mitigating the potential effects of confounders.
Considering age, sex, education, FTD subtypes and severity of dementia, we employed PSM technique to match the bilingual FTD group with the monolingual FTD group in a 1:1 ratio, yielding 26 bilinguals and 26 monolinguals. The optimal pair-matching algorithm available in the MatchIt package (Ho et al., Reference Ho, Imai, King and Stuart2011) on R version 4.2.3 was utilized for this matching procedure (codes are provided in the supplementary materials).
2.4. Image acquisition
All participants underwent MRI using a 3 Tesla Skyra MR scanner (Siemens, Erlangen, Germany), equipped with a 32-channel head coil. To minimize head movement and ensure participant comfort, foam pads were used to secure participants’ heads during the scanning process. Anatomical images were acquired using a three-dimensional (3D) T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) sequence. This sequence consisted of 192 sections, a repetition time (TR) of 2300 ms, an echo time (TE) of 2.98 ms, an inversion time (TI) of 900 ms, a slice thickness of 1 mm, a flip angle of 9 degrees, a field of view of 250 × 250 mm, a matrix resolution of 256 × 256 and voxel size was isotropic 1.0 × 1.0 × 1.0 mm3. In addition to the 3D T1-weighted MPRAGE sequence, fluid-attenuated inversion recovery and T2-weighted sequences were obtained to rule out any incidental findings, such as brain lesions in patients’ brains.
2.5. Region-based morphometry
The T1-weighted images of each participant were initially inspected for any inhomogeneity or movement-related artifacts. The pre-processing was performed using the default pipeline focused on voxel-based morphometry in the Computational Anatomy Toolbox (CAT12; http://dbm.neuro.uni-jena.de/cat/; Gaser et al., Reference Gaser, Dahnke, Thompson, Kurth, Luders and Initiative2022). The images were segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using the tissue probability maps provided in the toolbox. The intensity non-uniformities were corrected using the Adaptive Maximum A Posterior technique (see Figure S1, supplementary materials). Images were subjected to spatial normalization on the Montreal Neurological Institute (MNI) template using the DARTEL registration algorithm. After pre-processing, the CAT12 quality control (QC) tools were used to assess image quality and identify potential artifacts. The pre-processed images, along with any flagged images from the QC step, were visually inspected to identify potential artifacts or errors in pre-processing. In this process, five participants with significant artifacts or errors were excluded from subsequent analyses. In the process of extracting regions of interest (ROIs), the Hammers atlas (Hammers et al., Reference Hammers, Allom, Koepp, Free, Myers, Lemieux, Mitchell, Brooks and Duncan2003) was utilized for volume estimation of various frontal, temporal and subcortical ROI. This well-established anatomical atlas is specifically designed to enable accurate parcellation and labelling of brain structures in MRI images (see Figure S1, supplementary materials). By integrating the Hammers atlas into the analysis pipeline, we were able to efficiently isolate and examine particular ROI in the brain. The total intracranial volume (TIV) was estimated using the volumes of grey matter, white matter and CSF.
2.6. Statistical analyses
The statistical analyses were performed using SPSS version 26. Shapiro–Wilk test was used to check for normality of the data separately between bilinguals and monolinguals. The demographic, clinical and cognitive differences between bilinguals and monolinguals were assessed using t-test or Mann–Whitney U test for continuous variables and using Chi-square test for categorical variables. For the comparison of regional brain volumes between bilinguals and monolinguals, t-tests were used (see Table 2, for the list of regions that were analysed). Those regions revealing a significant difference between bilinguals and monolinguals were taken as the dependent variables for a multivariate general linear model. In the model, bilingualism, age, sex, education, severity of dementia and TIV were considered as the independent variables. Parameter estimates and univariate analyses were assessed only if the multivariate model was significant. For the post hoc analyses, Bonferroni corrected p-values are reported to adjust for multiple comparisons. Interaction effects of bilingualism with the other variables were also analysed. The regional brain volumes that demonstrated a difference between bilinguals and monolinguals were subjected to Pearson’s correlation with ACE III scores to understand the contribution of these regions to cognitive functioning. A significance threshold of p < 0.05 was considered.
3. Results
3.1. Demographic, clinical and cognitive profile
Among the 68 persons with FTD, the mean age was 58.57 ± 9.36 years and the male/female ratio was 37:31. There were 42 bilinguals and 26 monolinguals. Fifty persons had bvFTD and 18 were diagnosed to have PPA. In the cohort, 14 very mild, 29 mild, 19 moderate and 6 severe cases of FTD were recorded with a mean duration of illness of 32.19 ± 27.03 months.
In the unmatched dataset (see Table 1), bilinguals and monolinguals with FTD had comparable mean age at presentation (p = .342). The bilinguals with FTD were predominantly males (p = .013), had lesser severity of the disease (p = .049) and had better cognitive functioning (p = .015) compared to monolinguals. There were no significant differences between bilinguals and monolinguals in the proportion of FTD subtypes (p = .779) or duration of disease (p = .210).
Demographic, clinical and cognitive profile of bilinguals and monolinguals with FTD
Note: Continuous variables are represented as mean (SD), categorical variables as frequency (%). bvFTD: behavioural variant Frontotemporal dementia; PPA: Primary Progressive Aphasia; CDR: Clinical Dementia Rating; ACE-III: Addenbrooke’s Cognitive Examination-III
After PSM, there were no significant differences between bilinguals and monolinguals with FTD in their age (p = .633), in the distribution of males and females (p = .262), FTD subtype (p = .749), duration of disease (p = .317), dementia severity (p = .356) or cognitive performance (p = .354) (see Table 1).
3.2. Bilingualism and regional brain volumes
The frontal and temporal regions did not show any significant difference between bilinguals and monolinguals (see Table 2). Among the subcortical regions, bilinguals with FTD had greater loss of volume in the bilateral thalamus compared to monolinguals (left thalamus: t (50) = −2.36, p = .022, d = .92; right thalamus: t (50) = −2.88, p = .006, d = .86; see Figure 1A). The multivariate model was significant for bilingualism (F (1,45) = 4.383, p = .018, ηp2 = .166) and dementia severity (F (1,45) = 5.894, p = .005, ηp2 = .211). Bilingualism was associated with greater loss of bilateral thalamic volume (left thalamus: F (1,45) = 7.11, p = .022, ηp2 = .136; right thalamus: F (1,45) = 8.22, p = .012, ηp2 = .155, Bonferroni-corrected). Severity of dementia was associated with greater loss of bilateral thalamic volume (left thalamus: β = −.594, t = −3.472, p = .002; right thalamus: β = −.419, t = −2.476, p = .034, Bonferroni-corrected). There were no main effects of age (F (1,45) = .112, p = .894, ηp2 = .005), sex (F (1,45) = .991, p = .379, ηp2 = .043), years of education (F (1,45) = .540, p = .587, ηp2 = .024) or TIV (F (1,45) = 2.581, p = .087, ηp2 = .105). Furthermore, there were no interactions of bilingualism with severity of dementia (F (1,44) = 2.321, p = .110, ηp2 = .097), age (F (1,44) = 2.347, p = .108, ηp2 = .098), sex (F (1,44) = .340, p = .713, ηp2 = .016), years of education (F (1,44) = .279, p = .758, ηp2 = .013) or TIV (F (1,44) = .870, p = .426, ηp2 = .039).
Differences between bilingual and monolingual FTD patients in the frontal, temporal and subcortical regions of interest
a p < 0.05, significant.
(A) Bar plot represents bilinguals with FTD exhibiting lesser volume in the left and right thalamus compared to monolinguals. Error bars represent standard error. (B) Scatter plots showing the left and right thalamus correlate positively with the ACE III score.
To investigate the effect of bilingualism on the thalamic volumes in the unmatched groups, the same multivariate analysis was performed on the unmatched dataset (n = 68). The multivariate model was significant for bilingualism (F (1,61) = 4.455, p = .016, ηp2 = .129) and dementia severity (F (1,61) = 7.834, p = .001, ηp2 = .207). Bilinguals with FTD had reduced bilateral thalamus compared to monolinguals after controlling for age, sex, years of education, clinical severity and TIV (left thalamus: F (1,61) = 8.022, p = .012, ηp2 = .116; right thalamus: F (1,61) = 7.758, p = .014, ηp2 = .113, Bonferroni-corrected). Severity of dementia was associated with greater loss of bilateral thalamic volume (left thalamus: β = −.549, t = −3.917, p < .001; right thalamus: β = −.354, t = −2.397, p = .040, Bonferroni-corrected).
We also found that the thalamus was positively correlated with the ACE III score indicating its involvement in cognitive abilities (left thalamus: r = .363, p = .002; right thalamus: r = .254, p = .037) (see Figure 1B).
4. Discussion
The current study employed volumetric analysis to examine the relationship between bilingualism and cognitive reserve in persons with FTD. The results showed that bilinguals with FTD exhibit reduced bilateral thalamic volumes in comparison to their monolingual counterparts, despite demonstrating similar cognitive ability. This indicates that bilinguals were able to endure greater atrophy of the thalamus than monolinguals, potentially owing to more efficient cognitive processing mechanisms (Abutalebi et al., Reference Abutalebi, Della Rosa, Green, Hernandez, Scifo, Keim, Cappa and Costa2012). Our results suggest that bilingualism is related to better cognitive reserve in the presence of FTD pathology. To the best of our knowledge, this is the first evidence to highlight the neural basis of cognitive reserve in bilinguals with FTD.
The observed reduction in thalamic volume among bilingual speakers with FTD was consistent in both matched and unmatched groups indicating the robustness of the study findings. In the unmatched dataset, bilinguals had lesser severity of the disease as well as better cognition despite having reduced thalamic volume, which is in concordance with the cognitive reserve hypothesis. Another strength of the study is that our observations were unaffected by age, sex, education, severity of dementia or total intracranial volume, which is in line with prior research on bilingualism and age of dementia onset (Alladi et al., Reference Alladi, Bak, Duggirala, Surampudi, Shailaja, Shukla, Chaudhuri and Kaul2013; Ramakrishnan et al., Reference Ramakrishnan, Mekala, Mamidipudi, Yareeda, Mridula, Bak, Alladi and Kaul2017). The findings of this study also align with the existing literature on AD, reporting more severe atrophy in bilinguals compared to demographically and cognitively matched monolinguals (Duncan et al., Reference Duncan, Nikelski, Pilon, Steffener, Chertkow and Phillips2018; Schweizer et al., Reference Schweizer, Ware, Fischer, Craik and Bialystok2012). In addition to the loss of regional brain volumes, hypometabolism is also a feature of neurodegeneration that compliments the atrophy of brain volumes in neurodegenerative diseases (Gordon et al., Reference Gordon, Rohrer and Fox2016; Johnson et al., Reference Johnson, Fox, Sperling and Klunk2012). In support to our findings, bilingual speakers with AD have been shown to have more severe hypometabolism, despite having similar or better cognitive performance compared to monolinguals (Perani et al., Reference Perani, Farsad, Ballarini, Lubian, Malpetti, Fracchetti, Magnani, March and Abutalebi2017; Sala et al., Reference Sala, Malpetti, Farsad, Lubian, Magnani, Frasca Polara, Epiney, Abutalebi, Assal, Garibotto and Perani2022).
This study implicates the thalamus as a potential neural marker for cognitive reserve related to bilingualism in persons with FTD. The thalamus consists of several nuclei that can be grouped into: anterior, medial, lateral, posterior and reticular (Morel, Reference Morel2007). While about 20% of the thalamic nuclei are designated for the relay of sensory information, the majority of the thalamic nuclei participate in the complex functions of the cortical and subcortical brain networks (Halassa, Reference Halassa2022). Over the past decades, the role of the thalamus in cognitive processes including speed of processing, memory consolidation and attentional control has been recognized (Toader et al., Reference Toader, Regalado, Li, Terceros, Yadav, Kumar, Satow, Hollunder, Bonito-Oliva and Rajasethupathy2023). Through the thalamocortical connections, the thalamus acts as a gatekeeper for regulating the flow of sensory information for cognitive processing. The thalamus has been shown to act as a hub for major neurocognitive networks such as the executive control network, default mode network and salience network through the anterior and dorsomedial nuclei (Kawabata et al., Reference Kawabata, Bagarinao, Watanabe, Maesawa, Mori, Hara, Ohdake, Masuda, Ogura, Kato, Koyama, Katsuno, Wakabayashi, Kuzuya, Hoshiyama, Isoda, Naganawa, Ozaki and Sobue2021) that are also affected in FTD.
Earlier studies have revealed structural adaptation of thalamus in healthy bilingual adults (Korenar et al., Reference Korenar, Treffers-Daller and Pliatsikas2023) with respect to age of acquisition of second language (L2), immersion in L2, contextual use of L2 and language switching (Burgaleta et al., Reference Burgaleta, Sanjuán, Ventura-Campos, Sebastian-Galles and Ávila2016; DeLuca, Rothman, Bialystok, et al., Reference DeLuca, Rothman and Pliatsikas2019; Korenar et al., Reference Korenar, Treffers-Daller and Pliatsikas2022; Pliatsikas et al., Reference Pliatsikas, DeLuca, Moschopoulou and Saddy2017). Recent findings have also demonstrated that bilingual speakers with mild cognitive impairment have a higher amplitude of spontaneous activity in the bilateral thalamus in comparison to monolingual individuals (Marin-Marin et al., Reference Marin-Marin, Palomar-García, Miró-Padilla, Adrián-Ventura, Aguirre, Villar-Rodríguez and Costumero2021). It is possible that the bilinguals in this study compensate for the reduced thalamic volume by exhibiting higher amplitudes of spontaneous activity to maintain cognitive status. The thalamus has also been deemed as an important component of the language control network in bilingual speakers (Abutalebi & Green, Reference Abutalebi and Green2016). It is postulated that this network is modulated by the demands of the interactional contexts identified in the adaptive control hypothesis (Green & Abutalebi, Reference Green and Abutalebi2013). The thalamus aids in selecting the appropriate words from the mental lexicon in bilinguals by engaging with the right inferior frontal gyrus, caudate and putamen (Abutalebi & Green, Reference Abutalebi and Green2016). This is primarily important because bilinguals have to resolve interference from the non-target language (Hoshino & Kroll, Reference Hoshino and Kroll2008; Mishra & Singh, Reference Mishra and Singh2016). High frequency of switching is a characteristic feature of the multilingual Indian population which requires conflict resolution and response selection, thereby engaging the thalamus constantly. Bilingual language switching and cognitive task switching have been shown to have shared activation involving the thalamus (Weissberger et al., Reference Weissberger, Gollan, Bondi, Clark and Wierenga2015). The constant juggling of languages in lifelong bilinguals exercises executive and attentional control which later in life manifests as a protective effect on cognitive decline (Bialystok, Reference Bialystok2021; Bialystok & Craik, Reference Bialystok and Craik2022).
Notably, we did not find any differences in the frontal and temporal regions. Frontal and temporal areas in FTD are not only disease-related areas but are also regions that are associated with brain reserve (i.e., better structural properties of the brain such as larger grey matter volume, density and cortical thickness) among bilingual older adults with normal cognition. In previous studies on healthy aging, greater brain reserve in frontal and temporal regions has been observed among bilinguals (Abutalebi et al., Reference Abutalebi, Canini, Della Rosa, Sheung, Green and Weekes2014; Abutalebi, Guidi, et al., Reference Abutalebi, Guidi, Borsa, Canini, Della Rosa, Parris and Weekes2015; Del Maschio et al., Reference Del Maschio, Sulpizio, Gallo, Fedeli, Weekes and Abutalebi2018; Olsen et al., Reference Olsen, Pangelinan, Bogulski, Chakravarty, Luk, Grady and Bialystok2015; Voits, Robson, et al., Reference Voits, Robson, Rothman and Pliatsikas2022). In AD, bilinguals have demonstrated the reduced structure of the disease-related temporo-parietal areas despite having better or similar cognitive abilities compared to monolinguals indicating cognitive reserve. From studies on reserve/resilience, it is clear that there is a transition from brain reserve (better structural integrity of the brain including greater volumes) to cognitive reserve (reduced structural integrity of the brain including smaller volumes) (Arenaza-Urquijo et al., Reference Arenaza-Urquijo, Wirth and Chételat2015; Liu et al., Reference Liu, Julkunen, Paajanen, Westman, Wahlund, Aitken, Sobow, Mecocci, Tsolaki, Vellas, Muehlboeck, Spenger, Lovestone, Simmons and Soininen2012) as disease progresses from normal cognition to dementia. The lack of differences in frontal and temporal volumes in our cohort of FTD patients may be explained by the transition from the initial brain reserve (greater frontal and temporal volumes) observed in older adults with normal cognition to a stage of cognitive reserve (reduced volumes) among bilinguals with dementia. We hypothesise that during this transition phase, the structure of the brain may not show differences in the frontotemporal brain volumes.
The brain reserve advantage found among bilingual older adults has not been observed in the subcortical regions such as the thalamus. According to the predictions of the DRM (Pliatsikas, Reference Pliatsikas2020), the thalamus contracts following the peak efficiency stage of second language proficiency, especially in a population known for a high frequency of switching. The bilingual anterior-to-posterior and subcortical shift hypothesis (Grundy et al., Reference Grundy, Anderson and Bialystok2017) recognizes this inverted U-shaped relationship between subcortical grey matter volume and second language expertise. The reduced thalamic volumes among bilinguals in our FTD cohort is a novel finding and supports its role in providing cognitive reserve. We also found that the greater the thalamic volume, the better the cognitive functioning. Therefore, with lesser thalamic volumes in bilinguals compared to monolinguals, we would assume that bilinguals will have reduced cognitive functioning. However, bilinguals with FTD demonstrated similar cognitive performance compared to their monolingual counterparts, despite having this structural disadvantage of the thalamus.
The present study has certain limitations. Firstly, both bvFTD and PPA cases were included under the broad category of FTD. The initial symptoms and the pattern of progression of PPA are different from that of bvFTD. Therefore, it would be ideal to consider these two subtypes of FTD as different groups. The CDR may not adequately reflect the unique characteristics of PPA. This grouping also poses a problem when utilizing CDR as a method to evaluate the severity of the disease. However, CDR provides a useful common framework for assessing disease severity in a heterogeneous FTD cohort. Secondly, we used a simple but standard definition of bilingualism, encompassing the ability to meet societal communicative demands by engaging with interlocutors in more than one language (Mohanty, Reference Mohanty1994). This definition underscores the sociocultural perspective of bilingualism and has been previously employed in Indian studies of bilingualism among healthy older adults as well as persons with aphasia, mild cognitive impairment and dementia (Alladi et al., Reference Alladi, Bak, Duggirala, Surampudi, Shailaja, Shukla, Chaudhuri and Kaul2013; Lahiri et al., Reference Lahiri, Ardila, Dubey, Mukherjee, Chatterjee and Ray2021; Paplikar et al., Reference Paplikar, Mekala, Bak, Dharamkar, Alladi and Kaul2019, Reference Paplikar, Alladi, Varghese, Mekala, Arshad, Sharma, Saroja, Divyaraj, Dutt, Ellajosyula, Ghosh, Iyer, Sunitha, Kandukuri, Kaul, Khan, Mathew, Menon and Nandi2021; Ramakrishnan et al., Reference Ramakrishnan, Mekala, Mamidipudi, Yareeda, Mridula, Bak, Alladi and Kaul2017). Furthermore, bilingualism is now considered to represent a spectrum of experiences influenced by social context, taking into account factors such as the age of second language acquisition, language proficiency and language switching (DeLuca, Rothman, Bialystok, et al., Reference DeLuca, Rothman, Bialystok and Pliatsikas2019; Titone & Tiv, Reference Titone and Tiv2023). India is a country of linguistic diversity where the majority of individuals learn a second language through societal engagement from an early age, attain proficiency in speaking and engage in language switching including code-switching practices (Annamalai, Reference Annamalai2001; Bhatia & Ritchie, Reference Bhatia and Ritchie2006). Gathering data regarding language acquisition, proficiency and switching from individual dementia patients is often challenging and involves the risk of bias due to recall errors. Another potential limitation is that we did not measure functional connectivity in the cohort, to further establish neural mechanisms of cognitive reserve. Longitudinal examination of larger cohorts and inclusion of both structural and functional brain measures along with the investigation of genetic and pathological biomarkers will further expand our understanding of cognitive reserve due to bilingualism in dementia.
To conclude, this is the first study to investigate the neural basis of bilingualism among persons with FTD. The findings provide evidence supporting the notion of cognitive reserve in bilingual individuals with FTD by demonstrating that bilinguals exhibit equivalent levels of cognition in the presence of reduced thalamic structure. Our study also lends support to the theory that the early recruitment of executive and attentional control in bilinguals can facilitate protective mechanisms in the presence of neurodegenerative disease pathology. The findings of this study open up new avenues for further research in bilingualism and cognitive reserve in FTD as well as in other neurodegenerative diseases.
Supplementary material
To view supplementary material for this article, please visit http://doi.org/10.1017/S136672892500015X.
Data availability statement
The data that support the findings of this study are available here: https://osf.io/67vmq/?view_only=7f6be97c13984b94b0772d43e3e6bffc
Acknowledgements
The authors thank the participants and their caregivers for their participation in the study. This study was funded by Cognitive Science Research Initiative of the Department of Science and Technology (DST), Govt. of India (DST/CSRI/2017/368). We also thank Arijit Bhattacharya and Sandeep Kumar for helping in the clinical data compilation for this study.
Competing interests
The authors declare none.
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